Fully Automated Flow Protocol for C(sp)-C(sp) Bond Formation from Tertiary Amides and Alkyl Halides

Overview

Journal Org Lett

Publisher American Chemical Society

Specialties Biochemistry
Chemistry

Date 2023 May 23

PMID 37219892

Authors

Brenda Pijper

Raul Martin

Alberto J Huertas-Alonso

Maria Lourdes Linares

Enol Lopez

Josep Llaveria

Angel Diaz-Ortiz

Darren J Dixon

Antonio de la Hoz

Jesus Alcazar

Affiliations

Soon will be listed here.

Abstract

Herein, we present a novel C(sp)-C(sp) bond-forming protocol via the reductive coupling of abundant tertiary amides with organozinc reagents prepared from their corresponding alkyl halides. Using a multistep fully automated flow protocol, this reaction could be used for both library synthesis and target molecule synthesis on the gram-scale starting from bench-stable reagents. Additionally, excellent chemoselectivity and functional group tolerance make it ideal for late-stage diversification of druglike molecules.

References

Tahara A, Kitahara I, Sakata D, Kuninobu Y, Nagashima H . Donor-Acceptor π-Conjugated Enamines: Functional Group-Compatible Synthesis from Amides and Their Photoabsorption and Photoluminescence Properties. J Org Chem. 2019; 84(23):15236-15254. DOI: 10.1021/acs.joc.9b02267. View

Berton M, Huck L, Alcazar J . On-demand synthesis of organozinc halides under continuous flow conditions. Nat Protoc. 2018; 13(1):324-334. DOI: 10.1038/nprot.2017.141. View

Smith J, Harwood S, Baran P . Radical Retrosynthesis. Acc Chem Res. 2018; 51(8):1807-1817. PMC: 6349421. DOI: 10.1021/acs.accounts.8b00209. View

Xie L, Dixon D . Tertiary amine synthesis reductive coupling of amides with Grignard reagents. Chem Sci. 2017; 8(11):7492-7497. PMC: 5676097. DOI: 10.1039/c7sc03613b. View

Sun S, Jia Q, Zhang Z . Applications of amide isosteres in medicinal chemistry. Bioorg Med Chem Lett. 2019; 29(18):2535-2550. DOI: 10.1016/j.bmcl.2019.07.033. View

Laybourn A, Robertson K, Slater A . Quid Pro Flow. J Am Chem Soc. 2023; 145(8):4355-4365. PMC: 9983017. DOI: 10.1021/jacs.2c13670. View

McCann L, Hunter H, Clyburne J, Organ M . Higher-order zincates as transmetalators in alkyl-alkyl negishi cross-coupling. Angew Chem Int Ed Engl. 2012; 51(28):7024-7. DOI: 10.1002/anie.201203547. View

Dombrowski A, Aguirre A, Shrestha A, Sarris K, Wang Y . The Chosen Few: Parallel Library Reaction Methodologies for Drug Discovery. J Org Chem. 2021; 87(4):1880-1897. DOI: 10.1021/acs.joc.1c01427. View

He Y, Wang X . Synthesis of Cyclic Amidines by Iridium-Catalyzed Deoxygenative Reduction of Lactams and Tandem Reaction with Sulfonyl Azides. Org Lett. 2020; 23(1):225-230. DOI: 10.1021/acs.orglett.0c03953. View

10.

Zhang X, Smith R, Le C, McCarver S, Shireman B, Carruthers N . Copper-mediated synthesis of drug-like bicyclopentanes. Nature. 2020; 580(7802):220-226. PMC: 7148169. DOI: 10.1038/s41586-020-2060-z. View

11.

Hadei N, Achonduh G, Valente C, OBrien C, Organ M . Differentiating C-Br and C-Cl bond activation by using solvent polarity: applications to orthogonal alkyl-alkyl Negishi reactions. Angew Chem Int Ed Engl. 2011; 50(17):3896-9. DOI: 10.1002/anie.201100705. View

12.

Abdiaj I, Canellas S, Dieguez A, Linares M, Pijper B, Fontana A . End-to-End Automated Synthesis of C(sp)-Enriched Drug-like Molecules Negishi Coupling and Novel, Automated Liquid-Liquid Extraction. J Med Chem. 2022; 66(1):716-732. PMC: 9841985. DOI: 10.1021/acs.jmedchem.2c01646. View

13.

Fuentes de Arriba A, Lenci E, Sonawane M, Formery O, Dixon D . Iridium-Catalyzed Reductive Strecker Reaction for Late-Stage Amide and Lactam Cyanation. Angew Chem Int Ed Engl. 2017; 56(13):3655-3659. DOI: 10.1002/anie.201612367. View

14.

Capaldo L, Wen Z, Noel T . A field guide to flow chemistry for synthetic organic chemists. Chem Sci. 2023; 14(16):4230-4247. PMC: 10132167. DOI: 10.1039/d3sc00992k. View

15.

Trillo P, Slagbrand T, Adolfsson H . Straightforward α-Amino Nitrile Synthesis Through Mo(CO) -Catalyzed Reductive Functionalization of Carboxamides. Angew Chem Int Ed Engl. 2018; 57(38):12347-12351. DOI: 10.1002/anie.201807735. View

16.

Liu M, Chen K, Christian D, Fatima T, Pissarnitski N, Streckfuss E . High-throughput purification platform in support of drug discovery. ACS Comb Sci. 2011; 14(1):51-9. DOI: 10.1021/co200138h. View

17.

Yamazaki K, Gabriel P, Di Carmine G, Pedroni J, Farizyan M, Hamlin T . General Pyrrolidine Synthesis via Iridium-Catalyzed Reductive Azomethine Ylide Generation from Tertiary Amides and Lactams. ACS Catal. 2021; 11(12):7489-7497. PMC: 8291578. DOI: 10.1021/acscatal.1c01589. View

18.

Liu W, Lavagnino M, Gould C, Alcazar J, MacMillan D . A biomimetic S2 cross-coupling mechanism for quaternary sp-carbon formation. Science. 2021; 374(6572):1258-1263. PMC: 8926084. DOI: 10.1126/science.abl4322. View

19.

Schwarzwalder G, Matier C, Fu G . Enantioconvergent Cross-Couplings of Alkyl Electrophiles: The Catalytic Asymmetric Synthesis of Organosilanes. Angew Chem Int Ed Engl. 2019; 58(11):3571-3574. PMC: 6399024. DOI: 10.1002/anie.201814208. View

20.

Nakajima M, Sato T, Chida N . Iridium-catalyzed chemoselective reductive nucleophilic addition to N-methoxyamides. Org Lett. 2015; 17(7):1696-9. DOI: 10.1021/acs.orglett.5b00664. View