{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T07:15:54Z","timestamp":1790234154496,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2015,4,16]],"date-time":"2015-04-16T00:00:00Z","timestamp":1429142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Molecules"],"abstract":"<jats:p>The Kinugasa reaction has become an efficient method for the direct synthesis of \u03b2-lactams from substituted nitrones and copper(I) acetylides. In recent years, the reaction scope has been expanded to include the use of water as the solvent, and with micelle-promoted [3+2] cycloadditions followed by rearrangement furnishing high yields of \u03b2-lactams. The high yields of stable products under aqueous conditions render the modified Kinugasa reaction amenable to metabolic labelling and bioorthogonal applications. Herein, the development of methods for use of the Kinugasa reaction in aqueous media is reviewed, with emphasis on its potential use as a bioorthogonal coupling strategy.<\/jats:p>","DOI":"10.3390\/molecules20046959","type":"journal-article","created":{"date-parts":[[2015,4,16]],"date-time":"2015-04-16T10:37:57Z","timestamp":1429180677000},"page":"6959-6969","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Kinugasa Reactions in Water: From Green Chemistry to Bioorthogonal Labelling"],"prefix":"10.3390","volume":"20","author":[{"given":"Mariya","family":"Chigrinova","sequence":"first","affiliation":[{"name":"Life Sciences Division, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"MacKenzie","sequence":"additional","affiliation":[{"name":"Life Sciences Division, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada"},{"name":"Department of Chemistry, University of Ottawa, Ottawa, ON K1N 6N5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Sherratt","sequence":"additional","affiliation":[{"name":"Life Sciences Division, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Cheung","sequence":"additional","affiliation":[{"name":"Life Sciences Division, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada"},{"name":"Department of Chemistry, University of Ottawa, Ottawa, ON K1N 6N5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Paul","family":"Pezacki","sequence":"additional","affiliation":[{"name":"Life Sciences Division, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada"},{"name":"Department of Chemistry, University of Ottawa, Ottawa, ON K1N 6N5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,4,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1039\/B921630H","article-title":"Nitrones as dipoles for rapid strain-promoted 1,3-dipolar cycloadditions with cyclooctynes","volume":"46","author":"McKay","year":"2010","journal-title":"Chem. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9422","DOI":"10.1002\/anie.201003761","article-title":"Readily accessible bicyclononynes for bioorthogonal labeling and three-dimensional imaging of living cells","volume":"49","author":"Dommerholt","year":"2010","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1002\/anie.201106775","article-title":"Site-specific conjugation of scFvs antibodies to nanoparticles by bioorthogonal strain-promoted alkyne-nitrone cycloaddition","volume":"51","author":"Colombo","year":"2012","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3066","DOI":"10.1039\/c2ob07165g","article-title":"Kinetics studies of rapid strain-promoted [3+2]-cycloadditions of nitrones with biaryl-aza-cyclooctynone","volume":"10","author":"McKay","year":"2012","journal-title":"Org. Biomol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2772","DOI":"10.1039\/c3ob00043e","article-title":"N-terminal dual protein functionalization by strain-promoted alkyne-nitrone cycloaddition","volume":"11","author":"Temming","year":"2013","journal-title":"Org. Biomol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1139\/cjc-2013-0577","article-title":"Kinetics studies of rapid strain-promoted [3+2] cycloadditions of nitrones with bicyclo[6.1.0]nonyne","volume":"92","author":"MacKenzie","year":"2014","journal-title":"Can. J. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ding, L.K., and Irwin, W.J. (1976). Cis- and trans-azetidin-2-ones from nitrones and copper acetylide. J. Chem. Soc. Perkin Trans. 1, 2382\u20132386.","DOI":"10.1039\/p19760002382"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kinugasa, M., and Hashimoto, S. (1972). The reactions of copper(I) phenylacetylide with nitrones. J. Chem. Soc. Chem. Commun., 466\u2013467.","DOI":"10.1039\/c39720000466"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7817","DOI":"10.1016\/j.tet.2014.06.024","article-title":"Kinugasa reaction: An \u2018ugly duckling\u2019 of \u03b2-lactam chemistry","volume":"70","author":"Stecko","year":"2014","journal-title":"Tetrahedron"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1039\/C3RA43861A","article-title":"Novel achievements with an old metal: Copper-promoted synthesis of four-membered azacycles","volume":"4","author":"Alcaide","year":"2014","journal-title":"RSC Adv."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7664","DOI":"10.1002\/ejoc.201300597","article-title":"Kinugasa reaction: A direct one-pot route to highly functionalized \u03b2-lactams","volume":"2013","author":"Khangarot","year":"2013","journal-title":"Eur. J. Org. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1016\/j.tetlet.2009.02.035","article-title":"Studies of multicomponent Kinugasa reactions in aqueous media","volume":"50","author":"McKay","year":"2009","journal-title":"Tetrahedron Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"46966","DOI":"10.1039\/C4RA07851A","article-title":"Copper-catalysed cycloaddition reactions of nitrones and alkynes for bioorthogonal labelling of living cells","volume":"4","author":"Sherratt","year":"2014","journal-title":"RSC Adv."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"14846","DOI":"10.1073\/pnas.2335201100","article-title":"A metabolic labeling approach toward proteomic analysis of mucin-type o-linked glycosylation","volume":"100","author":"Hang","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6974","DOI":"10.1002\/anie.200900942","article-title":"Bioorthogonal chemistry: Fishing for selectivity in a sea of functionality","volume":"48","author":"Sletten","year":"2009","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1021\/cb6003228","article-title":"A comparative study of bioorthogonal reactions with azides","volume":"1","author":"Agard","year":"2006","journal-title":"ACS Chem. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"17993","DOI":"10.1021\/ja2083027","article-title":"Cellular consequences of copper complexes used to catalyze bioorthogonal click reactions","volume":"133","author":"Kennedy","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1021\/ja809451w","article-title":"Cellular lipid metabolism is influenced by the coordination environment of copper","volume":"131","author":"Kennedy","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/j.chembiol.2014.09.002","article-title":"Click chemistry in complex mixtures: Bioorthogonal bioconjugation","volume":"21","author":"McKay","year":"2014","journal-title":"Chem. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"16793","DOI":"10.1073\/pnas.0707090104","article-title":"Copper-free click chemistry for dynamic in vivo imaging","volume":"104","author":"Baskin","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3065","DOI":"10.1002\/anie.201000408","article-title":"Protein modification by strain-promoted alkyne-nitrone cycloaddition","volume":"49","author":"Ning","year":"2010","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"13518","DOI":"10.1021\/ja8053805","article-title":"Tetrazine ligation: Fast bioconjugation based on inverse-electron-demand Diels-Alder reactivity","volume":"130","author":"Blackman","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1021\/bc8004446","article-title":"Tetrazine-based cycloadditions: Application to pretargeted live cell imaging","volume":"19","author":"Devaraj","year":"2008","journal-title":"Bioconjugate Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2141","DOI":"10.1021\/ol006054v","article-title":"A \u201ctraceless\u201d Staudinger ligation for the chemoselective synthesis of amide bonds","volume":"2","author":"Saxon","year":"2000","journal-title":"Org. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1002\/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5","article-title":"Click chemistry: Diverse chemical function from a few good reactions","volume":"40","author":"Kolb","year":"2001","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2596","DOI":"10.1002\/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4","article-title":"A stepwise Huisgen cycloaddition process: Copper(I)-catalyzed regioselective \u201cligation\u201d of azides and terminal alkynes","volume":"41","author":"Rostovtsev","year":"2002","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7561","DOI":"10.1002\/chem.201204373","article-title":"Asymmetric synthesis of trans-\u03b2-lactams by a Kinugasa reaction on water","volume":"19","author":"Chen","year":"2013","journal-title":"Chem. Eur. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1021\/ja410756b","article-title":"Direct observation of reduction of Cu(II) to Cu(I) by terminal alkynes","volume":"136","author":"Zhang","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4999","DOI":"10.1021\/jo00121a018","article-title":"Copper-catalyzed reaction of terminal alkynes with nitrones. Selective synthesis of 1-aza-1-buten-3-yne and 2-azetidinone derivatives","volume":"60","author":"Miura","year":"1995","journal-title":"J. Org. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ye, M.-C., Zhou, J., Huang, Z.-Z., and Tang, Y. (2003). Chiral tris(oxazoline)\/Cu(II) catalyzed coupling of terminal alkynes and nitrones. Chem. Commun., 2554\u20132555.","DOI":"10.1039\/b306653c"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1055\/s-2007-980383","article-title":"Kinugasa reaction under click chemistry conditions","volume":"2007","author":"Basak","year":"2007","journal-title":"Synlett"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4659","DOI":"10.1039\/C4CC00660G","article-title":"Glycans in pathogenic bacteria - potential for targeted covalent therapeutics and imaging agents","volume":"50","author":"Tra","year":"2014","journal-title":"Chem. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Grammel, M., and Hang, H.C. (2013). Chemical reporters for biological discovery. Nat. Chem. Biol., 9.","DOI":"10.1038\/nchembio.1296"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e43850","DOI":"10.1371\/journal.pone.0043850","article-title":"Evaluation of 14 organic solvents and carriers for screening applications in zebrafish embryos and larvae","volume":"7","author":"Maes","year":"2012","journal-title":"PLoS ONE"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/BF00125572","article-title":"Inhibition of metabolic cooperation in Chinese hamster V79 cells by various organic solvents and simple compounds","volume":"1","author":"Chen","year":"1984","journal-title":"Cell Biol. Toxicol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.biotechadv.2011.04.002","article-title":"Organic solvent adaptation of gram positive bacteria: Applications and biotechnological potentials","volume":"29","author":"Torres","year":"2011","journal-title":"Biotechnol. Adv."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4697","DOI":"10.1002\/chem.201304056","article-title":"Synthesis of 18F-labelled \u03b2-lactams by using the Kinugasa reaction","volume":"20","author":"Zlatopolskiy","year":"2014","journal-title":"Chem. Eur. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7759","DOI":"10.1021\/ma400913a","article-title":"Multifunctionalization of polymers by strain-promoted cycloadditions","volume":"46","author":"Ledin","year":"2013","journal-title":"Macromolecules"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3143","DOI":"10.1002\/anie.201108127","article-title":"Click-mediated labeling of bacterial membranes through metabolic modification of the lipopolysaccharide inner core","volume":"51","author":"Dumont","year":"2012","journal-title":"Angew. Chem. Int. Ed."}],"updated-by":[{"DOI":"10.3390\/molecules20058303","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2015,4,16]],"date-time":"2015-04-16T00:00:00Z","timestamp":1429142400000}}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/20\/4\/6959\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T06:51:16Z","timestamp":1754290276000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/20\/4\/6959"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,4,16]]},"references-count":39,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2015,4]]}},"alternative-id":["molecules20046959"],"URL":"https:\/\/doi.org\/10.3390\/molecules20046959","relation":{"correction":[{"id-type":"doi","id":"10.3390\/molecules20058303","asserted-by":"object"}]},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,4,16]]}}}