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The inherent challenges associated with overriding the influence of the embedded N\u2010atom within pyridines was overcome using\n                    <jats:italic>n\u2010<\/jats:italic>\n                    butylsodium, which provided an avenue to deprotonate and functionalize the C4\u2010position over traditionally observed addition products that are formed with organolithium bases. In this work, we show that freshly generated 4\u2010sodiopyrdines could undergo transition metal free alkylation reactions directly with a variety of primary alkyl halides bearing diverse functional groups. In addition, after transmetalation to zinc chloride a simple and efficient Negishi cross\u2010coupling protocol was formulated for a variety of aromatic and heteroaromatic halides. The robustness of this protocol was demonstrated through the late\u2010stage installation of 4\u2010pyridyl fragments into a variety of complex active pharmaceutical ingredients including loratadine and prochlorperazine. Furthermore, through rapid injection NMR investigations, we are able to directly observe the evolution of anionic intermediates and determined that two distinct mechanistic pathways lead to the observed site selectivity: (1) the C4\u2010H within 2,6\u2010disubstituted pyridines could be removed directly and (2) the C4 selectivity of unsubstituted pyridine originates from the intermolecular exchange of metalation sites\n                    <jats:italic>via<\/jats:italic>\n                    a thermodynamic pathway.\n                  <\/jats:p>","DOI":"10.1002\/anie.202424172","type":"journal-article","created":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T12:12:52Z","timestamp":1735906372000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Functionalization of Pyridines at the C4 Position\n                    <i>via<\/i>\n                    Metalation and Capture"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6644-5999","authenticated-orcid":false,"given":"Han\u2010Hsiang","family":"Hsu","sequence":"first","affiliation":[{"name":"Department of Chemistry Texas A&amp;M University  PO Box 30012 College Station TX 77842-30012"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0122-4383","authenticated-orcid":false,"given":"Seokmin","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Chemistry Texas A&amp;M University  PO Box 30012 College Station TX 77842-30012"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2956-1464","authenticated-orcid":false,"given":"Cheng\u2010Chun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chemistry Texas A&amp;M University  PO Box 30012 College Station TX 77842-30012"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0135-8365","authenticated-orcid":false,"given":"Md Raja","family":"Sk","sequence":"additional","affiliation":[{"name":"Department of Chemistry Texas A&amp;M University  PO Box 30012 College Station TX 77842-30012"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6336-5566","authenticated-orcid":false,"given":"Andy A.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Chemistry Texas A&amp;M University  PO Box 30012 College Station TX 77842-30012"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,16]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm501100b"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b01807"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adj5331"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2021.102100"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm00013a022"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600640614"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.7b00021"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja710766j"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(01)97768-3"},{"key":"e_1_2_8_10_1","first-page":"1216","author":"Chichibabin A.","year":"1914","journal-title":"J. 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