Copper(I)-Catalyzed Cross-Coupling of 1-Bromoalkynes with N-Heterocyclic Organozinc Reagents

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2022 Jul 27

PMID 35889434

Authors

Christian Frabitore

Jerome Lepeule

Tom Livinghouse

Affiliations

Soon will be listed here.

Abstract

Nitrogen-containing heterocycles represent the majority of FDA-approved small-molecule pharmaceuticals. Herein, we describe a synthetic method to produce saturated N-heterocyclic drug scaffolds with an internal alkyne for elaboration. The treatment of N,N-dimethylhydrazinoalkenes with EtZn, followed by a Cu(I)-catalyzed cross-coupling with 1-bromoalkynes, results in piperidines and pyrrolidines with a good yield. Five examples are reported and a proposed mechanism for the Cu(I)-catalyzed cross-coupling is presented.

References

Meanwell N . Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety. Chem Res Toxicol. 2011; 24(9):1420-56. DOI: 10.1021/tx200211v. View

Klapars A, Antilla J, Huang X, Buchwald S . A general and efficient copper catalyst for the amidation of aryl halides and the N-arylation of nitrogen heterocycles. J Am Chem Soc. 2001; 123(31):7727-9. DOI: 10.1021/ja016226z. View

Roughley S, Jordan A . The medicinal chemist's toolbox: an analysis of reactions used in the pursuit of drug candidates. J Med Chem. 2011; 54(10):3451-79. DOI: 10.1021/jm200187y. View

Gao Y, Wu G, Zhou Q, Wang J . Palladium-Catalyzed Oxygenative Cross-Coupling of Ynamides and Benzyl Bromides by Carbene Migratory Insertion. Angew Chem Int Ed Engl. 2018; 57(10):2716-2720. DOI: 10.1002/anie.201712795. View

Welsch M, Snyder S, Stockwell B . Privileged scaffolds for library design and drug discovery. Curr Opin Chem Biol. 2010; 14(3):347-61. PMC: 2908274. DOI: 10.1016/j.cbpa.2010.02.018. View

Hinds E, Wolfe J . A Cross-Metathesis/Aza-Michael Reaction Strategy for the Synthesis of Cyclic and Bicyclic Ureas. J Org Chem. 2018; 83(17):10668-10676. DOI: 10.1021/acs.joc.8b01492. View

Sunsdahl B, Smith A, Livinghouse T . Intramolecular metalloamination of N,N-dimethylhydrazinoalkenes: a versatile method to access functionalized piperidines and pyrrolidines. Angew Chem Int Ed Engl. 2014; 53(52):14352-6. DOI: 10.1002/anie.201407768. View

Surry D, Buchwald S . Diamine Ligands in Copper-Catalyzed Reactions. Chem Sci. 2012; 1(1):13-31. PMC: 3289286. DOI: 10.1039/C0SC00107D. View

Thapa S, Shrestha B, Gurung S, Giri R . Copper-catalysed cross-coupling: an untapped potential. Org Biomol Chem. 2015; 13(17):4816-27. DOI: 10.1039/c5ob00200a. View

10.

Nicolai S, Sedigh-Zadeh R, Waser J . Pd(0)-catalyzed alkene oxy- and aminoalkynylation with aliphatic bromoacetylenes. J Org Chem. 2013; 78(8):3783-801. DOI: 10.1021/jo400254q. View

11.

Wolfe J . Palladium-Catalyzed Carboetherification and Carboamination Reactions of γ-Hydroxy- and γ-Aminoalkenes for the Synthesis of Tetrahydrofurans and Pyrrolidines. European J Org Chem. 2010; 2007(4):571-582. PMC: 2890284. View

12.

de la Torre B, Albericio F . The Pharmaceutical Industry in 2021. An Analysis of FDA Drug Approvals from the Perspective of Molecules. Molecules. 2022; 27(3). PMC: 8839730. DOI: 10.3390/molecules27031075. View

13.

Shikora J, Um C, Khoder Z, Chemler S . Saturated oxygen and nitrogen heterocycles oxidative coupling of alkyltrifluoroborates with alkenols, alkenoic acids and protected alkenylamines. Chem Sci. 2020; 10(40):9265-9269. PMC: 7003886. DOI: 10.1039/c9sc02835h. View

14.

Vitaku E, Smith D, Njardarson J . Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J Med Chem. 2014; 57(24):10257-74. DOI: 10.1021/jm501100b. View

15.

Babij N, Boothe J, McKenna G, Fornwald R, Wolfe J . Stereocontrolled synthesis of bicyclic ureas and sulfamides via Pd-catalyzed alkene carboamination reactions. Tetrahedron. 2019; 75(32):4228-4243. PMC: 6924926. DOI: 10.1016/j.tet.2019.04.031. View

16.

Nicolai S, Waser J . Pd(0)-catalyzed oxy- and aminoalkynylation of olefins for the synthesis of tetrahydrofurans and pyrrolidines. Org Lett. 2011; 13(23):6324-7. DOI: 10.1021/ol2029383. View

17.

de la Torre B, Albericio F . The Pharmaceutical Industry in 2020. An Analysis of FDA Drug Approvals from the Perspective of Molecules. Molecules. 2021; 26(3). PMC: 7865374. DOI: 10.3390/molecules26030627. View

18.

Sunsdahl B, Mickelsen K, Zabawa S, Anderson B, Livinghouse T . 1,2-Disubstituted Alkenes as Migratory Insertion Participants in Zn(II)-Promoted Metalloamination/Cyclization of N,N-Dimethylhydrazinoalkenes. J Org Chem. 2016; 81(21):10160-10164. DOI: 10.1021/acs.joc.6b01328. View

19.

Mickelsen K, Zabawa S, Livinghouse T . Diethylzinc-Mediated Metalloamination-Alkylation of , -Dimethylhydrazinoalkenes. Catalysis of C-Zn Alkylation Using Simple Cu(I) Salts. Synlett. 2019; 29(2):181-184. PMC: 6502506. DOI: 10.1055/s-0036-1588578. View

20.

Frabitore C, Lepeule J, Towey B, Livinghouse T, Robinson W . Efficient Reductions of Dimethylhydrazones using Preformed Primary Amine Boranes. Synth Commun. 2023; 52(2):185-189. PMC: 10488297. DOI: 10.1080/00397911.2021.2008449. View