Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Oct 7;12(19):11547-11556.
doi: 10.1021/acscatal.2c03498. Epub 2022 Sep 8.

General and Practical Route to Diverse 1-(Difluoro)alkyl-3-aryl Bicyclo[1.1.1]pentanes Enabled by an Fe-Catalyzed Multicomponent Radical Cross-Coupling Reaction

Angel Rentería-Gómez  1 , Wes Lee  2 , Shuai Yin  1 , Michael Davis  2 , Achyut Ranjan Gogoi  1 , Osvaldo Gutierrez  3
Affiliations

General and Practical Route to Diverse 1-(Difluoro)alkyl-3-aryl Bicyclo[1.1.1]pentanes Enabled by an Fe-Catalyzed Multicomponent Radical Cross-Coupling Reaction

Angel Rentería-Gómez et al. ACS Catal. .

Abstract

Bicyclo[1.1.1]pentanes (BCPs) are of great interest to the agrochemical, materials, and pharmaceutical industries. In particular, synthetic methods to access 1,3-dicarbosubsituted BCP-aryls have recently been developed, but most protocols rely on the stepwise C-C bond formation via the initial manipulation of BCP core to make the BCP electrophile or nucleophile followed by a second step (e.g., transition-metal-mediated cross-coupling step) to form the second key BCP-aryl bond. Moreover, despite the prevalence of C-F bonds in bioactive compounds, one-pot, multicomponent cross-coupling methods to directly functionalize [1.1.1]propellane to the corresponding fluoroalkyl BCP-aryl scaffolds are lacking. In this work, we describe a conceptually different approach to access diverse (fluoro)alkyl BCP-aryls at low temperatures and fast reaction times enabled by an iron-catalyzed multicomponent radical cross-coupling reaction from readily available (fluoro)alkyl halides, [1.1.1]propellane, and Grignard reagents. Further, experimental and computational mechanistic studies provide insights into the mechanism and ligand effects on the nature of C-C bond formation. Finally, these studies are used to develop a method to rapidly access synthetic versatile (difluoro)alkyl BCP halides via bisphosphine-iron catalysis.

Keywords: cross-couplings; dicarbofunctionalization; iron; multicomponent; sustainable catalysis.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1.
Scheme 1.
Cross-Coupling Methods to Construct 1,3-Difunctionalized-Substituted BCP-Aryls
Scheme 2.
Scheme 2.
Scope of Bisphosphine- and Diamine-Iron Catalytic Systems to Construct 1,3-Difunctionalized Substituted BCP-Aryls
Scheme 3.
Scheme 3.
(A) Computational Studies on the Ligand Effects (Red Using dpe and Blue Using dcpe) on the Mechanism of Three-Component Alkyl-Arylation of BCP (A); (B) Comparison of the Relevant Lowest Energy Radical Addition and Reductive Elimination Transition-State Structures Demonstrating Similar Energetic Profiles and Transition States for the C− C Bond Formation with Bisphosphine- and Diamine-Iron Catalytic Systems; and (C) Proposed Catalytic Cycle
Scheme 4.
Scheme 4.
Substrate Scope of Bisphosphine-Fe-Catalyzed Atom-Transfer Radical Addition (ATRA) to [1.1.1]Propellanea aReactions were carried out using 1 (0.2 mmol), 2 (0.4 mmol), 3a (0.1 mmol), FeCl2 (10 mol %), dcpe (20 mol %), THF (0.2 mL) at 0 °C under an argon atmosphere, and isolated yields were reported. b1H NMR yield (in parentheses) determined using 1,2-dibromomethane as an internal standard. cSimilar yields were obtained in the absence of FeCl2, dcpe, and 3a.
Scheme 5.
Scheme 5.
Control Reactions to Shed Light into the Role of Iron and Ligand in the Atom-Transfer Radical Addition Reaction Using [1.1.1]-Propellane as a Radical Acceptora a1H NMR yield determined using 1,2-dibromomethane as an internal standard.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Mykhailiuk PK Saturated bioisosteres of benzene: where to go next? Org. Biomol. Chem 2019, 17, 2839–2849. - PubMed
    2. Locke GM; Bernhard SSR; Senge MO Nonconjugated Hydrocarbons as Rigid-Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry. Chem. − Eur. J 2019, 25, 4590–4647. - PubMed
    1. Pellicciari R; Raimondo M; Marinozzi M; Natalini B; Costantino G; Thomsen C (S)-(+)-2-(3′-Carboxybicyclo[1.1.1]pentyl)-glycine, a Structurally New Group I Metabotropic Glutamate Receptor Antagonist. J. Med. Chem 1996, 39, 2874–2876. - PubMed
    2. Stepan AF; Subramanyam C; Efremov IV; Dutra JK; O’Sullivan TJ; DiRico KJ; McDonald WS; Won A; Dorff PH; Nolan CE; Becker SL; Pustilnik LR; Riddell DR; Kauffman GW; Kormos BL; Zhang L; Lu Y; Capetta SH; Green ME; Karki K; Sibley E; Atchison KP; Hallgren AJ; Oborski CE; Robshaw AE; Sneed B; O’Donnell CJ Application of the Bicyclo[1.1.1]pentane Motif as a Nonclassical Phenyl Ring Bioisostere in the Design of a Potent and Orally Active γ-Secretase Inhibitor. J. Med. Chem 2012, 55, 3414–3424. - PubMed
    3. Westphal MV; Wolfstaedter BT; Plancher J; Gatfield J; Carreira EM Evaluation of tert-Butyl isosteres: case studies of physicochemical and pharmacokinetic properties, efficacies, and activities. ChemMedChem 2015, 10, 461–469. - PubMed
    4. Costantino G; Maltoni K; Marinozzi M; Camaioni E; Prezeau L; Pin J-P; Pellicciari R Synthesis and biological evaluation of 2-(3′-(1H-tetrazol-5-yl)bicyclo[1.1.1]pent1yl)glycine (S-TBPG), a novel mGlu1 receptor antagonist. Bioorg. Med. Chem 2001, 9, 221–227. - PubMed
    5. Filosa R; Carmela Fulco M; Marinozzi M; Giacche N; Macchiarulo A; Peduto A; Massa A; de Caprariis P; Thomsen C; Christoffersen CT; Pellicciari R Design, synthesis and biological evaluation of novel bicyclo[1.1.1]pentane-based ω-acidic amino acids as glutamate receptors ligands. Bioorg. Med. Chem 2009, 17, 242–250. - PubMed
    6. Nicolaou KC; Vourloumis D; Totokotsopoulos S; Papakyriakou A; Karsunky H; Fernando H; Gavrilyuk J; Webb D; Stepan AF Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs. ChemMedChem 2016, 11, 31–37. - PubMed
    7. Nicolaou KC; Yin J; Mandal D; Erande RD; Klahn P; Jin M; Aujay M; Sandoval J; Gavrilyuk J; Vourloumis D Total Synthesis and Biological Evaluation of Natural and Designed Tubulysins. J. Am. Chem. Soc 2016, 138, 1698–1708. - PubMed
    8. Measom ND; Down KD; Hirst DJ; Jamieson C; Manas ES; Patel VK; Somers DO Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA2 Inhibitor. ACS Med. Chem. Lett 2017, 8, 43–48. - PMC - PubMed
    9. Goh YL; Cui YT; Pendharkar V; Adsool VA Toward Resolving the Resveratrol Conundrum: Synthesis and in Vivo Pharmacokinetic Evaluation of BCP-Resveratrol. ACS Med. Chem. Lett 2017, 8, 516–520. - PMC - PubMed
    10. Auberson YP; Brocklehurst C; Furegati M; Fessard TC; Koch G; Decker A; La Vecchia L; Briard E Improving Nonspecific Binding and Solubility: Bicycloalkyl Groups and Cubanes as para-Phenyl Bioisosteres. ChemMedChem 2017, 12, 590–598. - PubMed
    11. Wiberg KB; Waddell ST Reactions of [1.1.1]propellane. J. Am. Chem. Soc 1990, 112, 2194–2216.
    12. Ma X; Nhat Pham L Selective topics in the syntheses of bicyclo[1.1.1]pentane (BCP) analogues. Asian J. Org. Chem 2020, 9, 8–22.
    13. Kanazawa J; Uchiyama M Recent Advances in the Synthetic Chemistry of Bicyclo[1.1.1]pentane. Synlett 2019, 30, 1–11.
    14. Wiberg KB Small ring propellanes. Chem. Rev 1989, 89, 975–983.
    15. Dilmaç AM; Spuling E; de Meijere A; Brase S Propellanes- From a Chemical Curiosity to “Explosive” Materials and Natural Products. Angew. Chem., Int. Ed 2017, 56, 5684–5718. - PubMed
    16. Levin MD; Kaszynski P; Michl J Bicyclo[1.1.1]pentanes, [n]Staffanes, [1.1.1]Propellanes, and Tricyclo[2.1.0.0(2,5)]pentanes. Chem. Rev 2000, 100, 169–234. - PubMed
    17. Delia EW; Lochert IJ Synthesis of bridgehead-substituted bicyclo[1.1.1]pentanes. A review. Org. Prep. Proc. Int 1996, 28, 411–441.
    1. Rehm JDD; Ziemer B; Szeimies G A Facile Route to Bridgehead Disubstituted Bicyclo[1.1.1]pentanes Involving Palladium-Catalyzed Cross-Coupling Reactions. Eur. J. Org. Chem 1999, 1999, 2079–2085.
    1. Messner M; Kozhushkov SI; de Meijere A Nickel- and Palladium-Catalyzed Cross-Coupling Reactions at the Bridgehead of Bicyclo[1.1.1]pentane Derivatives- A Convenient Access to Liquid Crystalline Compounds Containing Bicyclo[1.1.1]pentane Moieties. Eur. J. Org. Chem 2000, 2000, 1137–1155.
    1. Makarov IS; Brocklehurst CE; Karaghiosoff K; Koch G; Knochel P Synthesis of Bicyclo[1.1.1]pentane Bioisosteres of Internal Alkynes and para-Disubstituted Benzenes from [1.1.1]Propellane. Angew. Chem., Int. Ed 2017, 56, 12774–12777. - PubMed
    2. Schwärzer K; Zipse H; Karaghiosoff K; Knochel P Highly Regioselective Addition ofAllylic Zinc Halides andVarious Zinc Enolates to [1.1.1]Propellane. Angew. Chem., Int. Ed 2020, 59, 20235–20241. - PMC - PubMed

LinkOut - more resources