{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:15:26Z","timestamp":1778544926149,"version":"3.51.4"},"reference-count":84,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2016,4,26]],"date-time":"2016-04-26T00:00:00Z","timestamp":1461628800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"European Union's Seventh Framework Programme","award":["FP7\/2007-2013"],"award-info":[{"award-number":["FP7\/2007-2013"]}]},{"name":"EFPIA companies"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Chemistry A European J"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Herein, we describe the versatile application of triphenylmethyl (trityl) isocyanide in multicomponent chemistry. This reagent can be employed as a cyanide source in the Strecker reaction and as convertible isocyanide in the preparation of <jats:italic>N<\/jats:italic>\u2010acyl amino acids by Ugi 4CR\/detritylation and free imidazo[1,2\u2010<jats:italic>a<\/jats:italic>]pyridin\u20103\u2010amines by a Groebke\u2013Blackburn\u2013Bienaym\u00e9 3CR condensation\/deprotection protocol. The mechanisms of these three classical MCRs intersect at the common <jats:italic>N<\/jats:italic>\u2010trityl nitrilium ion intermediate, whose predictable reactivity can be exploited towards chemoselective transformations.<\/jats:p>","DOI":"10.1002\/chem.201600285","type":"journal-article","created":{"date-parts":[[2016,4,26]],"date-time":"2016-04-26T22:08:01Z","timestamp":1461708481000},"page":"7837-7842","source":"Crossref","is-referenced-by-count":33,"title":["Trityl Isocyanide as a Mechanistic Probe in Multicomponent Chemistry: Walking the Line between Ugi\u2010 and Strecker\u2010type Reactions"],"prefix":"10.1002","volume":"22","author":[{"given":"R\u0103zvan C.","family":"Cioc","sequence":"first","affiliation":[{"name":"Department of Chemistry &amp; Pharmaceutical Sciences and Amsterdam Institute for Molecules Medicines and Systems (AIMMS) Vrije Universiteit Amsterdam  De Boelelaan 1108 1081 HZ Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans D.","family":"Preschel","sequence":"additional","affiliation":[{"name":"Department of Chemistry &amp; Pharmaceutical Sciences and Amsterdam Institute for Molecules Medicines and Systems (AIMMS) Vrije Universiteit Amsterdam  De Boelelaan 1108 1081 HZ Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gydo","family":"van\u2005der\u2005Heijden","sequence":"additional","affiliation":[{"name":"Department of Chemistry &amp; Pharmaceutical Sciences and Amsterdam Institute for Molecules Medicines and Systems (AIMMS) Vrije Universiteit Amsterdam  De Boelelaan 1108 1081 HZ Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1105-3947","authenticated-orcid":false,"given":"Eelco","family":"Ruijter","sequence":"additional","affiliation":[{"name":"Department of Chemistry &amp; Pharmaceutical Sciences and Amsterdam Institute for Molecules Medicines and Systems (AIMMS) Vrije Universiteit Amsterdam  De Boelelaan 1108 1081 HZ Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Romano V. A.","family":"Orru","sequence":"additional","affiliation":[{"name":"Department of Chemistry &amp; Pharmaceutical Sciences and Amsterdam Institute for Molecules Medicines and Systems (AIMMS) Vrije Universiteit Amsterdam  De Boelelaan 1108 1081 HZ Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,4,26]]},"reference":[{"key":"e_1_2_6_1_1","unstructured":"\u00a0"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.201402783"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr500099b"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr400615v"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.3987\/REV-13-781"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.201301715"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.3762\/bjoc.10.50"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1039\/C3CS60015G"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1039\/C5RA11531K"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1039\/C5RA08059B"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1039\/C4GC00013G"},{"key":"e_1_2_6_12_1","unstructured":"\u00a0"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1039\/C4CC10403J"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1039\/C5CC02749G"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201410605"},{"key":"e_1_2_6_15_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201410605"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.5b00131"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.5b00605"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.5b01502"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.5b01040"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201412074"},{"key":"e_1_2_6_20_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201412074"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1039\/C4RA10651B"},{"key":"e_1_2_6_22_1","first-page":"386","volume":"71","author":"Ugi K. I.","year":"1959","journal-title":"Angew. Chem."},{"key":"e_1_2_6_23_1","unstructured":"\u00a0"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-1998-1721"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(98)00653-4"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-3773(19980904)37:16<2234::AID-ANIE2234>3.0.CO;2-R"},{"key":"e_1_2_6_26_3","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-3757(19980817)110:16<2349::AID-ANGE2349>3.0.CO;2-W"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jlac.18500750103"},{"key":"e_1_2_6_28_1","unstructured":"\u00a0"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10870-012-0345-2"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00919a007"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00398a047"},{"key":"e_1_2_6_32_1","unstructured":"Ugi reactions are typically performed in alcoholic solvents. In this case a mixture of ethanol\/dichloromethane was used to improve the solubility of trityl isocyanide."},{"key":"e_1_2_6_33_1","unstructured":"As we observed that acetic acid does not protonate this imine under these conditions it is possible that the mechanism is not entirely identical to that of the reaction with trifluoroacetic acid as the acid component."},{"key":"e_1_2_6_34_1","unstructured":"See the Supporting Information for details. For catalytic Ugi 3CR reactions with water as the acid component see"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200800494"},{"key":"e_1_2_6_35_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.200800494"},{"key":"e_1_2_6_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2013.02.055"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1039\/c3ra23087b"},{"key":"e_1_2_6_38_1","unstructured":"Imine preformation was found to be important for high yields; unconverted amine buffers the reaction medium and reduces imine activation by the acid catalyst; furthermore nucleophilic amines compete with ethanol for the trityl cation; molecular sieves are required to trap the water that is released from the condensation and prevent the formation of the Ugi 3CR contaminant."},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2006.01.007"},{"key":"e_1_2_6_40_1","unstructured":"A similar problem was observed by Bienaym\u00e9 in the related imidazo[1 2-a]pyridine synthesis: see ref.\u2005[5c]."},{"key":"e_1_2_6_41_1","unstructured":"See the Supporting Information for detailed information."},{"key":"e_1_2_6_42_1","unstructured":"\u00a0"},{"key":"e_1_2_6_43_2","doi-asserted-by":"publisher","DOI":"10.1186\/2191-2858-1-11"},{"key":"e_1_2_6_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2013.11.035"},{"key":"e_1_2_6_45_2","doi-asserted-by":"publisher","DOI":"10.2174\/1570178611666140530221934"},{"key":"e_1_2_6_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2011.12.027"},{"key":"e_1_2_6_47_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10562-012-0958-2"},{"key":"e_1_2_6_48_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.201100089"},{"key":"e_1_2_6_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jorganchem.2012.02.005"},{"key":"e_1_2_6_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2010.05.088"},{"key":"e_1_2_6_51_2","doi-asserted-by":"publisher","DOI":"10.1002\/cjoc.201400635"},{"key":"e_1_2_6_52_1","unstructured":"The main disadvantage of this approach is the low atom economy; however recovery of trityl ethyl ether and its conversion back to the isocyanide greatly improves the overall atom economy of the process see also ref.\u2005[28]."},{"key":"e_1_2_6_53_1","unstructured":"This can also imply a different mechanism that bypasses the nitrilium ion intermediate; the mechanism of the Ugi reaction was calculated to circumvent charged intermediates in toluene:"},{"key":"e_1_2_6_54_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo2021554"},{"key":"e_1_2_6_55_2","doi-asserted-by":"publisher","DOI":"10.1039\/C3CC47156J"},{"key":"e_1_2_6_56_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.201403179"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201001592"},{"key":"e_1_2_6_57_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201001592"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00134a044"},{"key":"e_1_2_6_59_1","unstructured":"Interestingly tBuNC can also be used for this purpose: thetert-butyl analogue of Ugi product3\u2009awas deprotected directly to give carboxylic acid4\u2009ain a 52\u2009% yield but in this case the reaction was not clean."},{"key":"e_1_2_6_60_1","unstructured":"For bioactive imidazo[1 2-a]pyridin-3-amine derivatives see"},{"key":"e_1_2_6_61_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm501120z"},{"key":"e_1_2_6_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2012.07.052"},{"key":"e_1_2_6_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2011.05.062"},{"key":"e_1_2_6_64_1","unstructured":"\u00a0"},{"key":"e_1_2_6_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)00003-4"},{"key":"e_1_2_6_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2005.09.181"},{"key":"e_1_2_6_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2006.01.160"},{"key":"e_1_2_6_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2008.10.046"},{"key":"e_1_2_6_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2009.05.080"},{"key":"e_1_2_6_70_2","doi-asserted-by":"publisher","DOI":"10.1039\/c0ob00022a"},{"key":"e_1_2_6_71_2","doi-asserted-by":"publisher","DOI":"10.1039\/c2ob26733k"},{"key":"e_1_2_6_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2014.11.047"},{"key":"e_1_2_6_73_1","unstructured":"Thet-octyl substituted analogue gave no conversion under these conditions."},{"key":"e_1_2_6_74_1","unstructured":"The true one-pot procedure is possible but for convenience the molecular sieves were filtered off in between the two stages."},{"key":"e_1_2_6_75_1","unstructured":"\u00a0"},{"key":"e_1_2_6_76_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00967a005"},{"key":"e_1_2_6_77_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo01015a563"},{"key":"e_1_2_6_78_1","doi-asserted-by":"publisher","DOI":"10.1002\/macp.201400187"},{"key":"e_1_2_6_79_1","unstructured":"Trityl ethyl ether was recovered after the Strecker reaction (2\u2009g) and the GBB\/deprotection protocol (6\u2009i) in 85 and 83\u2009% yields respectively. 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