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. 2025 Mar 12;147(10):8969-8977.
doi: 10.1021/jacs.5c01108. Epub 2025 Mar 2.

Pd-Catalyzed Strain-Releasing Dyotropic Rearrangement: Ring-Expanding Amidofluorination of Methylenecyclobutanes

Baochao Yang  1 , Guoqiang Yang  1   2 , Qian Wang  1 , Jieping Zhu  1
Affiliations

Pd-Catalyzed Strain-Releasing Dyotropic Rearrangement: Ring-Expanding Amidofluorination of Methylenecyclobutanes

Baochao Yang et al. J Am Chem Soc. .

Abstract

Under the Pd(II)/Pd(IV) catalytic cycle, the cyclization of pent-4-en-1-amine derivatives typically yields either pyrrolidines or piperidines depending on the N-protecting group. We report herein an unprecedented Pd(II)-catalyzed oxidative domino process that converts readily accessible N-protected 2-(2-amidoethyl)-1-methylenecyclobutane derivatives to 1-fluoro-2-azabicyclo[3.2.1]octanes. This transformation constructs three chemical bonds under mild conditions [Pd(hfacac)2 (5.0 mol %), Selectfluor (2.0 equiv), MeCN, 60 °C, 10 min] through a domino sequence involving 5-exo-trig amidopalladation/Pd(II)-oxidation/chemoselective dyotropic rearrangement/C-F bond-forming reductive elimination. Notably, the cyclization mode remains independent of the N-protecting group under these conditions. Furthermore, diverse functional groups can be introduced at the bridgehead position of a bicyclic compound via an apparent anti-Bredt bridgehead iminium intermediate.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Pd(II)-Catalyzed Cyclization of Pent-4-en-1-amine Derivatives: Reaction Divergence
Abbreviations: protecting group (PG), amidopalladation (AP), dyotropic rearrangement (DR), phenyliodine(III) diacetate (PIDA), N-fluorobenzenesulfonimide (NFSI), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor), N-chlorosuccinimide (NCS).
Scheme 2
Scheme 2. From Methylenecyclobutanes to 2-Azabicyclo[3.2.1]octanes: Scope of Cyclobutane Substitutions
Reaction performed at 1.0 mmol scale with 1.0 mol % of Pd(hfacac)2, Pd(hfacac)2 = palladium hexafluoroacetylacetonate. Reaction conditions: 4 (0.1 mmol), Pd(hfacac)2 (5 mol %), and Selectfluor (0.2 mmol) in MeCN (2 mL, c 0.05), 60 °C, 10 min.
Scheme 3
Scheme 3. Scope of Substitutions on Amidoethyl Side Chain
Only the product resulting from the cyclization of the major diastereoisomer was isolated. Reagents and conditions: 4 (0.1 mmol), Pd(hfacac)2 (5 mol %), and Selectfluor (0.2 mmol) in MeCN (2 mL, c 0.05), 60 °C, 10 min.
Scheme 4
Scheme 4. From Methylenecyclopentane to 2-Azabicyclo[3.3.1]nonane
Reagents and conditions: 7 (0.1 mmol), Pd(hfacac)2 (5 mol %) and Selectfluor (0.2 mmol) in MeCN (2 mL, c 0.05), 60 °C, 10 min, flash column chromatography on silica gel, 70%. The same as conditions a, but purification was performed on a basic alumina column, 78%.
Scheme 5
Scheme 5. Mechanistic Studies
Scheme 6
Scheme 6. Chemical Transformation of 1-Fluoro-2-azabicyclo[3.2.1]octanes
Reagents and conditions: (a) TFA (5 equiv), DCM, rt, 10 h, 80%. (b) BF3·Et2O (3.0 equiv), allyltrimethylsilane (5.0 equiv), DCM, 0 °C, 2.5 h, 92%. (c) BF3·Et2O (3.0 equiv), potassium trifluoro(phenylethynyl)borate (2.0 equiv), TBAB (0.1 equiv), DCM, 0 °C, 1 h, 83%. (d) BF3·Et2O (3.0 equiv), (1-methoxyvinyl)oxy](trimethyl)silane (25 equiv), DCM, rt, 1.5 h, 56%. (e) BF3·Et2O (3.0 equiv), 2-(trimethylsilyloxy)furan (2.0 equiv), DCM, −10 °C, 1.5 h, 40% (dr 1.2:1) for 21, 22% for 22. (f) TiCl4 (2.0 equiv), DCM, 0 °C, 1.5 h, 96%. (g) BF3·Et2O (5.0 equiv), Et3SiH (10.0 equiv), DCM, rt, 2 h, 94%. (h) SmI2 (10.0 equiv), pyrrolidine (20.0 equiv), H2O (30 equiv), THF, rt, 1 h, 46% isolated yield, 73% NMR yield. Abbreviations: TFA = trifluoroacetic acid, DCM = dichloromethane, TBAB = tetrabutylammonium bromide, THF = tetrahydrofuran.
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