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. 2022 Mar 9;144(9):3939-3948.
doi: 10.1021/jacs.1c11921. Epub 2022 Feb 25.

Pd(II)-Catalyzed Enantioselective C(sp3)-H Arylation of Cyclopropanes and Cyclobutanes Guided by Tertiary Alkylamines

Jesus Rodrigalvarez  1 , Luke A Reeve  1 , Javier Miró  1 , Matthew J Gaunt  1
Affiliations

Pd(II)-Catalyzed Enantioselective C(sp3)-H Arylation of Cyclopropanes and Cyclobutanes Guided by Tertiary Alkylamines

Jesus Rodrigalvarez et al. J Am Chem Soc. .

Abstract

Strained aminomethyl-cycloalkanes are a recurrent scaffold in medicinal chemistry due to their unique structural features that give rise to a range of biological properties. Here, we report a palladium-catalyzed enantioselective C(sp3)-H arylation of aminomethyl-cyclopropanes and -cyclobutanes with aryl boronic acids. A range of native tertiary alkylamine groups are able to direct C-H cleavage and forge carbon-aryl bonds on the strained cycloalkanes framework as single diastereomers and with excellent enantiomeric ratios. Central to the success of this strategy is the use of a simple N-acetyl amino acid ligand, which not only controls the enantioselectivity but also promotes γ-C-H activation of over other pathways. Computational analysis of the cyclopalladation step provides an understanding of how enantioselective C-H cleavage occurs and revealed distinct transition structures to our previous work on enantioselective desymmetrization of N-isobutyl tertiary alkylamines. This straightforward and operationally simple method simplifies the construction of functionalized aminomethyl-strained cycloalkanes, which we believe will find widespread use in academic and industrial settings relating to the synthesis of biologically active small molecules.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(A) Selected pharmaceuticals containing cyclobutanes and cyclopropanes. (B) Selected C–H activation reactions on cyclobutanes and cyclopropanes. (C) Pd(II)-catalyzed enantioselective C(sp3)–H arylation of aminomethyl-cyclopropanes and -cyclobutanes directed by unbiased tertiary alkylamine.
Figure 2
Figure 2
Previous work on Pd(II)-catalyzed γ-C(sp3)–H arylation of tertiary alkylamines.
Figure 3
Figure 3
(A) Computational analysis of the enantiodetermining C–H cleavage on aminomethyl-cyclopropanes. Basis set B3LyP-D3(BJ)/[6-311+G(2d,p)/ SDD(Pd)]. (B) Proposed pathway for of aminomethyl-cyclopropanes via Pd(II)-catalyzed enantioselective γ-methylene-C(sp3)–H arylation.
Chart 1
Chart 1. Scope of Enantioselective γ-Methylene C(sp3)–H Arylation of Aminomethyl-cyclopropanes
Scheme 1
Scheme 1. Reaction of Racemic Disubstituted Aminomethyl-cyclopropanes to Form Enantioenriched Trisubstituted Products
Chart 2
Chart 2. (A, B) Scope of Enantioselective γ-Methylene C(sp3)–H Arylation of Aminomethyl-cyclobutanes and (C) Late-Stage Functionalization of Pharmaceutical Agents
Figure 4
Figure 4
Computational analysis of the enantiodetermining C–H cleavage in cyclobutane rings. Basis set B3LyP-D3(BJ)/[6-311+G(2d,p)/ SDD(Pd)].
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