{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T19:43:45Z","timestamp":1791402225888,"version":"4.3.3"},"reference-count":130,"publisher":"Wiley","issue":"56","license":[{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chemistry A European J"],"published-print":{"date-parts":[[2021,10,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The continuous flow reaction of various aryl or heteroaryl bromides in toluene in the presence of THF (1.0\u2005equiv) with <jats:italic>sec<\/jats:italic>\u2010BuLi (1.1\u2005equiv) provided at 25\u2009\u00b0C within 40\u2005sec the corresponding aryllithiums which were acylated with various functionalized <jats:italic>N<\/jats:italic>,<jats:italic>N<\/jats:italic>\u2010dimethylamides including easily enolizable amides at \u221220\u2009\u00b0C within 27\u2005sec, producing highly functionalized ketones in 48\u201390\u2009% yield (36 examples). This method was well suited for the preparation of \u03b1\u2010chiral ketones such as naproxene and ibuprofen derived ketones with 99\u2009% <jats:italic>ee<\/jats:italic>. A one\u2010pot stepwise bis\u2010addition of two different lithium organometallics to 1,1,3,3\u2010tetramethyurea (TMU) provided unsymmetrical ketones in 69\u201379\u2009% yield (9 examples).<\/jats:p>","DOI":"10.1002\/chem.202102805","type":"journal-article","created":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T08:50:41Z","timestamp":1628844641000},"page":"13977-13981","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Continuous Flow Acylation of (Hetero)aryllithiums with Polyfunctional <i>N<\/i>,<i>N<\/i>\u2010Dimethylamides and Tetramethylurea in Toluene"],"prefix":"10.1002","volume":"27","author":[{"given":"Dimitrije","family":"Djukanovic","sequence":"first","affiliation":[{"name":"Department Chemie Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen  Butenandtstra\u00dfe 5\u201313, Haus F 81377 Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Heinz","sequence":"additional","affiliation":[{"name":"Department Chemie Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen  Butenandtstra\u00dfe 5\u201313, Haus F 81377 Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Mandrelli","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG, Chemical Development Fabrikstra\u00dfe 4002 Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Mostarda","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG, Chemical Development Fabrikstra\u00dfe 4002 Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Filipponi","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG, Chemical Development Fabrikstra\u00dfe 4002 Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Martin","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG, Chemical Development Fabrikstra\u00dfe 4002 Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Knochel","sequence":"additional","affiliation":[{"name":"Department Chemie Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen  Butenandtstra\u00dfe 5\u201313, Haus F 81377 Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,9,9]]},"reference":[{"key":"e_1_2_2_1_1","unstructured":"\u00a0"},{"key":"e_1_2_2_2_2","unstructured":"P. Vogel in:Sci. Synth. Vol. 26 (Ed. J. Cossy) Thieme New York 2005 pp. 13\u201318;"},{"key":"e_1_2_2_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/9783527667512"},{"key":"e_1_2_2_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/adsc.201400630"},{"key":"e_1_2_2_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00795a055"},{"key":"e_1_2_2_6_1","unstructured":"\u00a0"},{"key":"e_1_2_2_7_2","first-page":"22","author":"Nahm S.","year":"1981","journal-title":"Tetrahedron Lett."},{"key":"e_1_2_2_8_2","doi-asserted-by":"publisher","DOI":"10.1039\/D0OB00813C"},{"key":"e_1_2_2_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(01)81368-X"},{"key":"e_1_2_2_10_1","unstructured":"\u00a0"},{"key":"e_1_2_2_11_2","first-page":"1414","author":"Martin R.","year":"1997","journal-title":"Synlett"},{"key":"e_1_2_2_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/ol8004326"},{"key":"e_1_2_2_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201710931"},{"key":"e_1_2_2_13_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201710931"},{"key":"e_1_2_2_14_1","unstructured":"\u00a0"},{"key":"e_1_2_2_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/1521-3773(20020902)41:17<3188::AID-ANIE3188>3.0.CO;2-H"},{"key":"e_1_2_2_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.6b00842"},{"key":"e_1_2_2_17_1","unstructured":"\u00a0"},{"key":"e_1_2_2_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00945a011"},{"key":"e_1_2_2_19_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-1984-30782"},{"key":"e_1_2_2_20_2","doi-asserted-by":"publisher","DOI":"10.1246\/bcsj.60.1027"},{"key":"e_1_2_2_21_2","doi-asserted-by":"publisher","DOI":"10.1039\/b412768d"},{"key":"e_1_2_2_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00298a035"},{"key":"e_1_2_2_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201709553"},{"key":"e_1_2_2_23_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201709553"},{"key":"e_1_2_2_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201814373"},{"key":"e_1_2_2_24_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201814373"},{"key":"e_1_2_2_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201801527"},{"key":"e_1_2_2_26_2","doi-asserted-by":"publisher","DOI":"10.1039\/C9CC03927A"},{"key":"e_1_2_2_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.202004840"},{"key":"e_1_2_2_28_1","unstructured":"\u00a0"},{"key":"e_1_2_2_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajoc.202000389"},{"key":"e_1_2_2_30_2","doi-asserted-by":"publisher","DOI":"10.1039\/C8OB00733K"},{"key":"e_1_2_2_31_1","unstructured":"\u00a0"},{"key":"e_1_2_2_32_2","doi-asserted-by":"publisher","DOI":"10.1039\/C5CC08507A"},{"key":"e_1_2_2_33_2","doi-asserted-by":"publisher","DOI":"10.1039\/C8CC08444K"},{"key":"e_1_2_2_34_2","doi-asserted-by":"publisher","DOI":"10.1039\/C9SC01817D"},{"key":"e_1_2_2_35_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0040-1705956"},{"key":"e_1_2_2_36_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.6b00134"},{"key":"e_1_2_2_37_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.8b01380"},{"key":"e_1_2_2_38_1","unstructured":"\u00a0"},{"key":"e_1_2_2_39_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.oprd.6b00292"},{"key":"e_1_2_2_40_2","doi-asserted-by":"publisher","DOI":"10.1556\/1846.2016.00034"},{"key":"e_1_2_2_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201901814"},{"key":"e_1_2_2_41_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201901814"},{"key":"e_1_2_2_42_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201706157"},{"key":"e_1_2_2_42_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201706157"},{"key":"e_1_2_2_43_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201202221"},{"key":"e_1_2_2_43_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201202221"},{"key":"e_1_2_2_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1264"},{"key":"e_1_2_2_45_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.oprd.7b00229"},{"key":"e_1_2_2_46_2","doi-asserted-by":"publisher","DOI":"10.1556\/1846.2017.00009"},{"key":"e_1_2_2_47_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201411728"},{"key":"e_1_2_2_47_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201411728"},{"key":"e_1_2_2_48_2","doi-asserted-by":"publisher","DOI":"10.1007\/s41981-018-0015-4"},{"key":"e_1_2_2_49_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201906462"},{"key":"e_1_2_2_49_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201906462"},{"key":"e_1_2_2_50_1","unstructured":"\u00a0"},{"key":"e_1_2_2_51_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201810158"},{"key":"e_1_2_2_51_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201810158"},{"key":"e_1_2_2_52_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202003392"},{"key":"e_1_2_2_52_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.202003392"},{"key":"e_1_2_2_53_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202012085"},{"key":"e_1_2_2_53_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.202012085"},{"key":"e_1_2_2_54_2","first-page":"12","author":"Heinz B.","year":"2021","journal-title":"Chem. Sci."},{"key":"e_1_2_2_55_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202103031"},{"key":"e_1_2_2_55_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.202103031"},{"key":"e_1_2_2_56_1","unstructured":"\u00a0"},{"key":"e_1_2_2_57_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201900743"},{"key":"e_1_2_2_58_2","doi-asserted-by":"publisher","DOI":"10.1039\/C5RA14890A"},{"key":"e_1_2_2_59_1","unstructured":"\u00a0"},{"key":"e_1_2_2_60_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201405014"},{"key":"e_1_2_2_60_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201405014"},{"key":"e_1_2_2_61_2","doi-asserted-by":"publisher","DOI":"10.1002\/adsc.201801228"},{"key":"e_1_2_2_62_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo402849z"},{"key":"e_1_2_2_63_1","unstructured":"\u00a0"},{"key":"e_1_2_2_64_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.9b04254"},{"key":"e_1_2_2_65_2","doi-asserted-by":"publisher","DOI":"10.1039\/D1OB00288K"},{"key":"e_1_2_2_66_1","unstructured":"\u00a0"},{"key":"e_1_2_2_67_2","first-page":"18","author":"Various","journal-title":"N,N"},{"key":"e_1_2_2_68_2","unstructured":"We concentrated our efforts on the atom economical dimethylamides but control experiments showed thatN N-diethylamides orN-morpholinoamides were also suitable substrates for these acylations while ethyl esters gave a significant amount of double addition see Supporting Information (page 17)."},{"key":"e_1_2_2_69_1","unstructured":"For a list of (hetero)aryl bromides of type8 (hetero)aryllithiums of type2and amides of type1and6 see Supporting Information (pages 4\u20135)."},{"key":"e_1_2_2_70_1","unstructured":"\u00a0"},{"key":"e_1_2_2_71_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201802123"},{"key":"e_1_2_2_71_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201802123"},{"key":"e_1_2_2_72_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201906898"},{"key":"e_1_2_2_72_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201906898"},{"key":"e_1_2_2_73_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202012496"},{"key":"e_1_2_2_73_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.202012496"},{"key":"e_1_2_2_74_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18188-z"},{"key":"e_1_2_2_75_1","unstructured":"\u00a0"},{"key":"e_1_2_2_76_2","unstructured":"Solvent Recovery Handbook (Ed.: I.\u2005M. Smallwood) Blackwell Science Ltd. Oxford 2002;"},{"key":"e_1_2_2_77_2","first-page":"2002","author":"Sassian M.","journal-title":"Appl. Organomet. Chem."},{"key":"e_1_2_2_78_2","doi-asserted-by":"publisher","DOI":"10.1021\/op060154k"},{"key":"e_1_2_2_79_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.201500757"},{"key":"e_1_2_2_80_1","unstructured":"For the preparation of various aryllithiums in toluene see:"},{"key":"e_1_2_2_81_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-328X(00)81121-3"},{"key":"e_1_2_2_82_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-328X(95)05990-7"},{"key":"e_1_2_2_83_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(99)00161-6"},{"key":"e_1_2_2_84_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo001246p"},{"key":"e_1_2_2_85_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2005.12.007"},{"key":"e_1_2_2_86_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2010.06.073"},{"key":"e_1_2_2_87_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201309841"},{"key":"e_1_2_2_87_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201309841"},{"key":"e_1_2_2_88_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja211944q"},{"key":"e_1_2_2_89_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201405879"},{"key":"e_1_2_2_89_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201405879"},{"key":"e_1_2_2_89_4","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.7b00423"},{"key":"e_1_2_2_90_2","doi-asserted-by":"publisher","DOI":"10.1039\/C9SC02314C"},{"key":"e_1_2_2_91_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.202000317"},{"key":"e_1_2_2_92_1","unstructured":"For the effect of toluene or THF on the enolization reaction during the addition of ArLi to amides see Supporting Information (page 16)."},{"key":"e_1_2_2_93_1","unstructured":"\u00a0"},{"key":"e_1_2_2_94_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.oprd.6b00247"},{"key":"e_1_2_2_95_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.oprd.7b00385"},{"key":"e_1_2_2_96_1","unstructured":"For the synthesis of [1.1.1]bicyclopentane derivatives using metalorganic chemistry see:"},{"key":"e_1_2_2_97_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.7b11865"},{"key":"e_1_2_2_98_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201706799"},{"key":"e_1_2_2_98_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201706799"},{"key":"e_1_2_2_99_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202009340"},{"key":"e_1_2_2_99_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.202009340"},{"key":"e_1_2_2_100_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201909655"},{"key":"e_1_2_2_100_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201909655"},{"key":"e_1_2_2_101_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b00557"},{"key":"e_1_2_2_102_1","doi-asserted-by":"publisher","DOI":"10.1002\/ardp.200700065"},{"key":"e_1_2_2_103_1","unstructured":"\u00a0"},{"key":"e_1_2_2_104_2","doi-asserted-by":"publisher","DOI":"10.2174\/157017807781024255"},{"key":"e_1_2_2_105_2","doi-asserted-by":"publisher","DOI":"10.1039\/C4SC00611A"},{"key":"e_1_2_2_106_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b03280"},{"key":"e_1_2_2_107_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo00008a057"},{"key":"e_1_2_2_108_1","unstructured":"For further screenings and optimizations of the continuous flow procedures see Supporting Information (pages 7\u201315)."}],"container-title":["Chemistry \u2013 A European Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/chem.202102805","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/chem.202102805","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/chem.202102805","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T10:58:54Z","timestamp":1760266734000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/chem.202102805"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,9]]},"references-count":130,"journal-issue":{"issue":"56","published-print":{"date-parts":[[2021,10,7]]}},"alternative-id":["10.1002\/chem.202102805"],"URL":"https:\/\/doi.org\/10.1002\/chem.202102805","archive":["Portico"],"relation":{},"ISSN":["0947-6539","1521-3765"],"issn-type":[{"value":"0947-6539","type":"print"},{"value":"1521-3765","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,9]]},"assertion":[{"value":"2021-08-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-09-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}