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Bromodifluoromethane, a simple and commercially available alkyl halide, is harnessed as an effective source of difluoromethyl radical by silyl\u2010radical\u2010mediated halogen abstraction. The merger of this fluoroalkyl electrophile activation pathway with a dual nickel\/photoredox catalytic platform enables the difluoromethylation of a diverse array of aryl and heteroaryl bromides under mild conditions. The utility of this procedure is showcased in the late\u2010stage functionalization of several drug analogues.<\/jats:p>","DOI":"10.1002\/anie.201807629","type":"journal-article","created":{"date-parts":[[2018,8,3]],"date-time":"2018-08-03T12:23:55Z","timestamp":1533299035000},"page":"12543-12548","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":191,"title":["Metallaphotoredox Difluoromethylation of Aryl Bromides"],"prefix":"10.1002","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3089-0692","authenticated-orcid":false,"given":"Vlad","family":"Bacauanu","sequence":"first","affiliation":[{"name":"Merck Center for Catalysis at Princeton University  Washington Road Princeton NJ 08544 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Cardinal","sequence":"additional","affiliation":[{"name":"Merck Center for Catalysis at Princeton University  Washington Road Princeton NJ 08544 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoshi","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Merck Center for Catalysis at Princeton University  Washington Road Princeton NJ 08544 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaru","family":"Kondo","sequence":"additional","affiliation":[{"name":"Merck Center for Catalysis at Princeton University  Washington Road Princeton NJ 08544 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David F.","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Merck Center for Catalysis at Princeton University  Washington Road Princeton NJ 08544 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Remy","sequence":"additional","affiliation":[{"name":"Merck Center for Catalysis at Princeton University  Washington Road Princeton NJ 08544 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6447-0587","authenticated-orcid":false,"given":"David W. C.","family":"MacMillan","sequence":"additional","affiliation":[{"name":"Merck Center for Catalysis at Princeton University  Washington Road Princeton NJ 08544 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,8,28]]},"reference":[{"key":"e_1_2_2_1_1","unstructured":"\u00a0"},{"key":"e_1_2_2_2_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm800219f"},{"key":"e_1_2_2_3_2","doi-asserted-by":"publisher","DOI":"10.1039\/B610213C"},{"key":"e_1_2_2_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.5b00392"},{"key":"e_1_2_2_5_1","unstructured":"\u00a0"},{"key":"e_1_2_2_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201206566"},{"key":"e_1_2_2_6_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201206566"},{"key":"e_1_2_2_7_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr500366b"},{"key":"e_1_2_2_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr1004293"},{"key":"e_1_2_2_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr500368h"},{"key":"e_1_2_2_10_1","unstructured":"\u00a0"},{"key":"e_1_2_2_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00111a021"},{"key":"e_1_2_2_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b01691"},{"key":"e_1_2_2_13_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.7b04457"},{"key":"e_1_2_2_14_1","unstructured":"\u00a0"},{"key":"e_1_2_2_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm1013693"},{"key":"e_1_2_2_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b01788"},{"key":"e_1_2_2_17_1","unstructured":"For recent reviews on difluoromethylation reactions see:"},{"key":"e_1_2_2_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/3418_2014_87"},{"key":"e_1_2_2_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201702311"},{"key":"e_1_2_2_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajoc.201600509"},{"key":"e_1_2_2_21_1","unstructured":"For selected examples see:"},{"key":"e_1_2_2_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja301013h"},{"key":"e_1_2_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6405"},{"key":"e_1_2_2_24_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b00053"},{"key":"e_1_2_2_25_2","doi-asserted-by":"publisher","DOI":"10.1039\/C7SC00691H"},{"key":"e_1_2_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.2746"},{"key":"e_1_2_2_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.7b02989"},{"key":"e_1_2_2_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.7b11976"},{"key":"e_1_2_2_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar7335"},{"key":"e_1_2_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03532-1"},{"key":"e_1_2_2_31_1","unstructured":"For reviews on metallaphotoredox catalysis see:"},{"key":"e_1_2_2_32_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.6b00018"},{"key":"e_1_2_2_33_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.6b00090"},{"key":"e_1_2_2_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41570-017-0052"},{"key":"e_1_2_2_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b04818"},{"key":"e_1_2_2_36_1","unstructured":"\u00a0"},{"key":"e_1_2_2_37_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00002a035"},{"key":"e_1_2_2_38_2","doi-asserted-by":"publisher","DOI":"10.1021\/ar00016a003"},{"key":"e_1_2_2_39_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules17010527"},{"key":"e_1_2_2_40_1","doi-asserted-by":"publisher","DOI":"10.1517\/13543776.2012.728587"},{"key":"e_1_2_2_41_1","unstructured":"\u00a0"},{"key":"e_1_2_2_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41557-018-0021-z"},{"key":"e_1_2_2_43_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.8b00183"},{"key":"e_1_2_2_44_1","doi-asserted-by":"publisher","DOI":"10.1201\/9781420007282"},{"key":"e_1_2_2_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(97)00527-9"},{"key":"e_1_2_2_46_1","unstructured":"dF(CF3)ppy=2-(2 4-difluorophenyl)-5-trifluoromethylpyridine; dtbbpy=4 4\u2032-di-t-Bu-2 2\u2032-bipyridine."},{"key":"e_1_2_2_47_1","doi-asserted-by":"publisher","DOI":"10.1021\/cm051312"},{"key":"e_1_2_2_48_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1255525"},{"key":"e_1_2_2_49_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr00002a004"},{"key":"e_1_2_2_50_1","unstructured":"Control experiments with aryl halide17revealed that light photocatalyst nickel and silane are all required for the success of the transformation (<1\u2009% yield in the absence of at least one component). Reduction of CF2HBr to CF2H2was observed when the nickel catalyst was excluded an observation that supports the capacity of the silyl radical to engage in halogen abstraction with CF2HBr. See the Supporting Information for details."},{"key":"e_1_2_2_51_1","unstructured":"The implementation of commercially available (bromodifluoromethyl)trimethylsilane as a CF2H source was also possible but not pursued because of lower reaction efficiency (Table\u20051)."},{"key":"e_1_2_2_52_1","unstructured":"For reports of proposed NiIcatalytic intermediates undergoing formal oxidative addition into bromodifluoromethane and chlorodifluoromethane see:"},{"key":"e_1_2_2_53_2","doi-asserted-by":"publisher","DOI":"10.1002\/cjoc.201700624"},{"key":"e_1_2_2_54_2","unstructured":"ref.\u2005[6i]."},{"key":"e_1_2_2_55_1","unstructured":"For experimental observations consistent with the deactivation of the nickel catalyst (i.e. poor conversion of starting material) see the Supporting Information."},{"key":"e_1_2_2_56_1","unstructured":"In support of the dramatic differences among the rates of oxidative addition competition experiments between16and18revealed that at early reaction time points the difluoromethyl product from electron-deficient18was obtained in up to 45\u2009% yield whereas electron-neutral bromoarene16remained entirely unreacted. See the Supporting Information."},{"key":"e_1_2_2_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201201244"},{"key":"e_1_2_2_57_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201201244"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fanie.201807629","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/am-pdf\/10.1002%2Fanie.201807629","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.201807629","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,11]],"date-time":"2023-09-11T10:21:25Z","timestamp":1694427685000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.201807629"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,28]]},"references-count":59,"journal-issue":{"issue":"38","published-print":{"date-parts":[[2018,9,17]]}},"alternative-id":["10.1002\/anie.201807629"],"URL":"https:\/\/doi.org\/10.1002\/anie.201807629","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,8,28]]},"assertion":[{"value":"2018-07-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-08-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}