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The transformation utilizes an acyloxyphosphonium ion as the active electrophile, conveniently generated in\u2005situ from the carboxylic acid substrate by using commodity chemicals. The utility of the reaction system is exemplified by its chemoselectivity, with tolerance to a variety of important functional groups. The late\u2010stage functionalization of carboxylic acid active pharmaceutical ingredients and pharmaceutically relevant compounds is also discussed.<\/jats:p>","DOI":"10.1002\/chem.202102854","type":"journal-article","created":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T12:35:41Z","timestamp":1630499741000},"page":"15908-15913","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Direct Synthesis of Tri\u2010\/Difluoromethyl Ketones from Carboxylic Acids by Cross\u2010Coupling with Acyloxyphosphonium Ions"],"prefix":"10.1002","volume":"27","author":[{"given":"Xanath","family":"Ispizua\u2010Rodriguez","sequence":"first","affiliation":[{"name":"Department of Chemistry Loker Hydrocarbon Research Institute University of Southern California  837 Bloom Walk Los Angeles CA-90089-1661 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5818-2404","authenticated-orcid":false,"given":"Socrates B.","family":"Munoz","sequence":"additional","affiliation":[{"name":"Department of Chemistry Kansas State University  322 CBC Bldg Manhattan KS66506-0401 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinayak","family":"Krishnamurti","sequence":"additional","affiliation":[{"name":"Department of Chemistry Loker Hydrocarbon Research Institute University of Southern California  837 Bloom Walk Los Angeles CA-90089-1661 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2896-1917","authenticated-orcid":false,"given":"Thomas","family":"Mathew","sequence":"additional","affiliation":[{"name":"Department of Chemistry Loker Hydrocarbon Research Institute University of Southern California  837 Bloom Walk Los Angeles CA-90089-1661 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6350-8325","authenticated-orcid":false,"given":"G. K. S.","family":"Prakash","sequence":"additional","affiliation":[{"name":"Department of Chemistry Loker Hydrocarbon Research Institute University of Southern California  837 Bloom Walk Los Angeles CA-90089-1661 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,10,5]]},"reference":[{"key":"e_1_2_2_1_1","unstructured":"\u00a0"},{"key":"e_1_2_2_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/9780470281895"},{"key":"e_1_2_2_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.9b03604"},{"key":"e_1_2_2_4_1","unstructured":"\u00a0"},{"key":"e_1_2_2_5_2","doi-asserted-by":"crossref","unstructured":"\u201cSynthetic Advances in Nucleophilic and Related Tri- and Difluoromethylation Protocols\u201d S.\u2005B. Munoz S. Krishnamoorthy T. Mathew G.\u2005K.\u2005S. Prakash inFrontiers of Organofluorine Chemistry(Ed.: I. 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Acyl bromide formation does not take place under our conditions; appreciable amounts of acyl bromides are only obtained from carboxylic acids PPh3and NBS in dioxane under reflux; see:"},{"key":"e_1_2_2_76_2","doi-asserted-by":"publisher","DOI":"10.1080\/10426509508042564"},{"key":"e_1_2_2_77_2","unstructured":"Unlike their acyl chloride counterparts the number of commercially available acyl bromides is severely limited. In contrast the parent carboxylic acids are indisputably widely available."},{"key":"e_1_2_2_78_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo00224a076"},{"key":"e_1_2_2_79_1","doi-asserted-by":"publisher","DOI":"10.3762\/bjoc.14.11"},{"key":"e_1_2_2_80_1","doi-asserted-by":"publisher","DOI":"10.3762\/bjoc.9.257"},{"key":"e_1_2_2_81_1","doi-asserted-by":"publisher","DOI":"10.1039\/p29830000297"},{"key":"e_1_2_2_82_1","unstructured":"\u00a0"},{"key":"e_1_2_2_83_2","unstructured":"This interesting result will be further pursued in future work;"},{"key":"e_1_2_2_84_2","unstructured":"We surmise that this observation is likely a result of the utilization of [CuCF3] as the nucleophilic \u2212CF3source; organocopper reagents are reluctant to engage in 1 2-additions;"},{"key":"e_1_2_2_85_2","first-page":"135","volume":"41","author":"Lipshutz B. H.","year":"1992","journal-title":"Org. 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For an elegant exception to this see ref.\u2005[31d] for a report on (NHC)CuCF2H preparation in THF\/alkoxide system; alkoxide bases were detrimental for our protocol."},{"key":"e_1_2_2_92_1","unstructured":"\u00a0"},{"key":"e_1_2_2_93_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b00053"},{"key":"e_1_2_2_94_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.6b01733"},{"key":"e_1_2_2_95_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfluchem.2007.05.015"},{"key":"e_1_2_2_96_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200804446"},{"key":"e_1_2_2_97_1","unstructured":"See the Supporting Information for full details."},{"key":"e_1_2_2_98_2","unstructured":"Chemical shifts of [CuCF3] are relative to internal standard PhOCF3(\u221258.0\u2005ppm)."},{"key":"e_1_2_2_99_1","unstructured":"\u00a0"},{"key":"e_1_2_2_100_2","first-page":"417","volume":"58","author":"Knochel P.","year":"2001","journal-title":"Org. 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