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Enantioenriched azaarylmethyl amine derivatives are useful building blocks in synthetic and medicinal chemistry. To access these valuable motifs, an enantioselective palladium-catalyzed benzylation of azaarylmethyl amine pronucleophiles is introduced. Of note, this is a rare application of asymmetric (2-naphthyl)methylation of pro-nucleophiles with high p K a values (p K a ≈ 34 in DMSO). Control experiments support the notion that the coordination of Li + to the azaaryl nitrogen plays a critical role in the substitution process. With this procedure, enantioenriched (2-naphthyl)methylene azaarylmethyl amines with a variety of azaaryl groups (pyridyl, pyrazine, quinoxaline and isoquinoline) and cyclic and acyclic amines are readily obtained with good yields and enantioselectivities up to 99%.
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Scope and Mechanistic Probe into Asymmetric Synthesis of α-Trisubstituted-α-Tertiary Amines by Rhodium Catalysis
Asymmetric reactions that convert racemic mixtures into enantioenriched amines are of significant importance due to the prevalence of amines in pharmaceuticals, with about 60% of drug candidates containing tertiary amines. Although transition metal catalyzed allylic substitution processes have been developed to provide access to enantioenriched α-disubstituted allylic amines, enantioselective synthesis of sterically demanding α-tertiary amines with a tetrasubstituted carbon stereocenter remains a major challenge. Herein, we report a chiral diene-ligated rhodium catalyzed asymmetric substitution of racemic tertiary allylic trichloroacetimidates with aliphatic secondary amines to afford α-trisubstituted-α-tertiary amines. Mechanistic investigation is conducted using synergistic experimental and computational studies. Density functional theory calculations show that the chiral diene-ligated rhodium promotes the ionization of tertiary allylic substrates to form both anti and syn π-allyl intermediates. The anti π-allyl pathway proceeds through a higher energy than the syn π-allyl pathway. The rate of conversion of the less reactive π-allyl intermediate to the more reactive isomer via π−σ−π interconversion was faster than the rate of nucleophilic attack onto the more reactive intermediate. These data imply that the Curtin−Hammett conditions are met in the amination reaction, leading to dynamic kinetic asymmetric transformation. Computational studies also show that hydrogen bonding interactions between β-oxygen of allylic substrate and amine-NH greatly assist the delivery of amine nucleophile onto more hindered internal carbon of the π-allyl intermediate. The synthetic utility of the current methodology is showcased by efficient preparation of α-trisubstituted-α-tertiary amines featuring pharmaceutically relevant secondary amine cores with good yields and excellent selectivities (branched−linear >99:1, up to 99% enantiomeric excess).
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- Award ID(s):
- 1856437
- PAR ID:
- 10500148
- Publisher / Repository:
- American Chemical Society
- Date Published:
- Journal Name:
- Journal of the American Chemical Society
- Volume:
- 145
- Issue:
- 36
- ISSN:
- 0002-7863
- Page Range / eLocation ID:
- 19642 to 19654
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1021/jacs.3c04211
