{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T15:59:39Z","timestamp":1790351979043,"version":"4.1.0"},"reference-count":29,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,17]],"date-time":"2022-07-17T00:00:00Z","timestamp":1658016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute for General Medical Science","award":["GM11694"],"award-info":[{"award-number":["GM11694"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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 Et2Zn, 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.<\/jats:p>","DOI":"10.3390\/molecules27144561","type":"journal-article","created":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T01:53:22Z","timestamp":1658109202000},"page":"4561","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Copper(I)-Catalyzed Cross-Coupling of 1-Bromoalkynes with N-Heterocyclic Organozinc Reagents"],"prefix":"10.3390","volume":"27","author":[{"given":"Christian","family":"Frabitore","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9rome","family":"L\u00e9peule","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Livinghouse","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1021\/tx200211v","article-title":"Improving Drug Candidates by Design: A Focus on Physicochemical Properties as a Means of Improving Compound Disposition and Safety","volume":"24","author":"Meanwell","year":"2011","journal-title":"Chem. Res. Toxicol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.cbpa.2010.02.018","article-title":"Privileged scaffolds for library design and drug discovery","volume":"14","author":"Welsch","year":"2010","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3451","DOI":"10.1021\/jm200187y","article-title":"The Medicinal Chemist\u2019s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates","volume":"54","author":"Roughley","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10257","DOI":"10.1021\/jm501100b","article-title":"Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals","volume":"57","author":"Vitaku","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"de la Torre, B.G., and Albericio, F. (2022). The Pharmaceutical Industry in 2021. An Analysis of FDA Drug Approvals from the Perspective of Molecules. Molecules, 27.","DOI":"10.3390\/molecules27031075"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"de la Torre, B.G., and Albericio, F. (2021). The Pharmaceutical Industry in 2020. An Analysis of FDA Drug Approvals from the Perspective of Molecules. Molecules, 26.","DOI":"10.3390\/molecules26030627"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nrd.2016.244","article-title":"Applications of chemogenomic library screening in drug discovery","volume":"16","author":"Jones","year":"2017","journal-title":"Nat. Rev. Drug. Discov."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1124\/pr.112.007336","article-title":"Computational Methods in Drug Discovery","volume":"66","author":"Sliwoski","year":"2012","journal-title":"Pharmacol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1055\/s-0036-1588578","article-title":"Diethylzinc-Mediated Metalloamination\u2013Alkylation of N,N-Dimethylhydrazinoalkenes Catalysis of C\u2013Zn Alkylation Using Simple Cu(I) Salts","volume":"29","author":"Mickelsen","year":"2018","journal-title":"Synlett"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10160","DOI":"10.1021\/acs.joc.6b01328","article-title":"1,2-Disubstituted Alkenes as Migratory Insertion Participants in Zn(II)-Promoted Metalloamination\/Cyclization of N,N-Dimethylhydrazinoalkenes","volume":"81","author":"Sunsdahl","year":"2016","journal-title":"J. Org. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"14352","DOI":"10.1002\/anie.201407768","article-title":"Intramolecular Metalloamination of N,N-Dimethylhydrazinoalkenes: A Versatile Method to Access Functionalized Piperidines and Pyrrolidines","volume":"53","author":"Sunsdahl","year":"2014","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4228","DOI":"10.1016\/j.tet.2019.04.031","article-title":"Stereocontrolled Synthesis of Bicyclic Ureas and Sulfamides via Pd-Catalyzed Alkene Carboamination Reactions","volume":"75","author":"Babij","year":"2019","journal-title":"Tetrahedron"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10668","DOI":"10.1021\/acs.joc.8b01492","article-title":"A Cross-Metathesis\/Aza-Michael Reaction Strategy for the Synthesis of Cyclic and Bicyclic Ureas","volume":"83","author":"Hinds","year":"2018","journal-title":"J. Org. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1002\/ejoc.200600767","article-title":"Palladium-Catalyzed Carboetherification and Carboamination Reactions of \u03b3-Hydroxy and \u03b3-Aminoalkenes for the Synthesis of Tetrahydrofurans and Pyrrolidines","volume":"4","author":"Wolfe","year":"2007","journal-title":"Eur. J. Org. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1055\/a-1308-0021","article-title":"Palladium-Catalyzed Functionalization of olefins and Alkynes: From Oxyalkynylation to Tethered Dynaimc Kinetic Asymmetric Transforamtions (DYKAT)","volume":"32","author":"Nicolai","year":"2021","journal-title":"Synlett"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3783","DOI":"10.1021\/jo400254q","article-title":"Pd(0)-Catalyzed Alkene Oxy- and Aminoalkynylation with Aliphatic Bromoacetylenes","volume":"78","author":"Nicolai","year":"2013","journal-title":"J. Org. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6324","DOI":"10.1021\/ol2029383","article-title":"Pd(0)-Catalyzed Oxy- and Aminoalkynylation of Olefins for the Synthesis of Tetrahydrofurans and Pyrrolidines","volume":"13","author":"Waser","year":"2011","journal-title":"Org. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9265","DOI":"10.1039\/C9SC02835H","article-title":"Saturated oxygen and nitrogen heterocycles via oxidative coupling of alkylfluroborates with alkenols, alkenoic acids and protected alkenylamines","volume":"40","author":"Shikora","year":"2019","journal-title":"Chem. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11311","DOI":"10.1021\/acs.joc.7b02072","article-title":"Stereoselective and Regioselective Synthesis of hetereocycles via Copper-Catalyzed Additions of Amine Derivatives and Alcohols to Alkenes","volume":"82","author":"Chemler","year":"2017","journal-title":"J. Org. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"9515","DOI":"10.1021\/jacs.7b05680","article-title":"R Direct Synthesis of 2-Formylpyrrolidines, 2-Pyrrolidinones and 2-Dihydrofuranones via Aerobic Copper-Catalyzed Aminooxygenation and deoxygenation of 4-Pentenylsulonaminds and 4-Pentenylalcohols","volume":"139","author":"Wdowik","year":"2017","journal-title":"J. Am. Chem. Soc."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4799","DOI":"10.1016\/S0040-4039(01)80511-6","article-title":"The Reactivity of Highly Functionalized Copper, Zinc Reagents RCu(CN)ZnI Toward 1-Haloalkynes and Acetylenic Esters","volume":"30","author":"Yeh","year":"1989","journal-title":"Tetrahedron Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4032","DOI":"10.1021\/ja00166a047","article-title":"Higher order cyanocuprates R2Cu(CN)Li2: Discrete reagents or lower order lithium cyanide (LiCN) modified Gilman cuprates?","volume":"112","author":"Lipshutz","year":"1990","journal-title":"J. Am. Chem. Soc."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Knochel, P., Millot, N., Rodriguez, A.L., and Tucker, C.E. (2004). Preparation and Applications of Functionalized Organozinc Compounds. Organic Reactions, John Wiley & Sons, Inc.","DOI":"10.1002\/chin.200319247"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4816","DOI":"10.1039\/C5OB00200A","article-title":"Copper-catalysed cross-coupling: An untapped potential","volume":"13","author":"Thapa","year":"2015","journal-title":"Org. Biomol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7727","DOI":"10.1021\/ja016226z","article-title":"A general and efficient copper catalyst for the amidation of aryl halides and the N-arylation of nitrogen heterocycles","volume":"123","author":"Klapars","year":"2001","journal-title":"J. Am. Chem. Soc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1039\/c0sc00107d","article-title":"Diamine ligands in copper-catalyzed reactions","volume":"1","author":"Surry","year":"2010","journal-title":"Chem. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1080\/00397911.2021.2008449","article-title":"Efficient reductions of dimethylhydrazones using preformed primary amine boranes","volume":"52","author":"Frabitore","year":"2022","journal-title":"Syn. Comm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2716","DOI":"10.1002\/anie.201712795","article-title":"Palladium-Catalyzed Oxygenative Cross-Coupling of Ynamide and Benzyl Bromides by Carbene Migratory Insertion","volume":"57","author":"Gao","year":"2018","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1002\/ejoc.201500138","article-title":"Nucleophile-Selective Cross-Coupling Reactions with Vinyl and Alkynyl Bromides on a Dinucleophilic Aromatic Substrate","volume":"11","author":"He","year":"2015","journal-title":"Eur. J. Org. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/14\/4561\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:52:35Z","timestamp":1760140355000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/14\/4561"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,17]]},"references-count":29,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["molecules27144561"],"URL":"https:\/\/doi.org\/10.3390\/molecules27144561","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,17]]}}}