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. 2020 Jun 24;142(25):11252-11269.
doi: 10.1021/jacs.0c04486. Epub 2020 Jun 11.

Evidence for Simultaneous Dearomatization of Two Aromatic Rings under Mild Conditions in Cu(I)-Catalyzed Direct Asymmetric Dearomatization of Pyridine

Michael W Gribble Jr  1 , Richard Y Liu  1 , Stephen L Buchwald  1
Affiliations

Evidence for Simultaneous Dearomatization of Two Aromatic Rings under Mild Conditions in Cu(I)-Catalyzed Direct Asymmetric Dearomatization of Pyridine

Michael W Gribble Jr et al. J Am Chem Soc. .

Abstract

Bis(phosphine) copper hydride complexes are uniquely able to catalyze direct dearomatization of unactivated pyridines with carbon nucleophiles, but the mechanistic basis for this result has been unclear. Here we show that, contrary to our initial hypotheses, the catalytic mechanism is monometallic and proceeds via dearomative rearrangement of the phenethylcopper nucleophile to a Cpara-metalated form prior to reaction at heterocycle C4. Our studies support an unexpected heterocycle-promoted pathway for this net 1,5-Cu-migration beginning with a doubly dearomative imidoyl-Cu-ene reaction. Kinetics, substituent effects, computational modeling, and spectroscopic studies support the involvement of this unusual process. In this pathway, the CuL2 fragment subsequently mediates a stepwise Cope rearrangement of the doubly dearomatized intermediate to the give the C4-functionalized 1,4-dihydropyridine, lowering a second barrier that would otherwise prohibit efficient asymmetric catalysis.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
C–C-Bond-forming dearomatization of pyridine.
Figure 2.
Figure 2.
Mechanistic proposals for Cu-catalyzed direct dearomatization.
Figure 3.
Figure 3.
Cu-catalyzed direct dearomatization occurs with regioselectivity opposite that predicted.
Figure 4.
Figure 4.
Development of an open bimetallic transition state model.
Figure 5.
Figure 5.
Phenethylcopper complexes are the MACS during dearomatization and exhibit mechanistically significant stereochemical dynamics.
Figure 6.
Figure 6.
Determination of the molecular formula for the TLTS of dearomatization of 1d using reaction kinetics.
Figure 7.
Figure 7.
The single-dearomatization pathway: Precedent and computed energy surface.
Figure 8:
Figure 8:
Models for Cpara-metalated intermediate 13aa and the 5,5-rearrangement transition state.
Figure 9.
Figure 9.
The 1,3-Cu-migration product 11a in the single-dearomatization pathway is predicted to undergo facile 1,2- addition.
Figure 10.
Figure 10.
Precedent for 1,4-dearomatization via an imidoyl-Cu-ene reaction of the phenethylcopper intermediate.
Figure 11.
Figure 11.
The double-dearomatization pathway.
Figure 12.
Figure 12.
Predicted qualitative double-dearomatization PES for heterocycles with very electron-withdrawing C3 substituents.
Figure 13:
Figure 13:
Saturation kinetics in the dearomatization of 1g imply an energy surface like that predicted for the double-dearomatization and similarly imply that 10gh should be observable.
Figure 14:
Figure 14:
The double-dearomatization mechanism predicts the correct diastereo- and enantio-selectivity.
Figure 15.
Figure 15.
Mechanistic basis for the styrene-para-group effect.
Scheme 1.
Scheme 1.
Simplified Catalytic Cycle for Rate-Law Derivations.
See this image and copyright information in PMC

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