DOI:10.1002/chem.201904794 Minireview & Organometallic Chemistry |Reviews Showcase| Recent Advances of the Halogen–Zinc Exchange Reaction MoritzBalkenhohl and PaulKnochel*[a] Chem. Eur.J.2020, 26,3688 –3697 3688 2019 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Minireview Abstract: For the preparation of zinc organometallics bear- gen–zinc exchange reaction is reported, with aspecial focus ing highly sensitive functional groups such as ketones,alde- lying on novel dialkylzinc reagents complexed with lithium hydes or nitro groups, especially mild halogen–zincex- alkoxides. Additionally,the preparation and application of change reagents have proventobeofgreat potential. In organofluorinezinc reagents and transition-metal-catalyzed this Minireview, the latestresearch in the area of the halo- halogen–zinc exchange reactions are reviewed. Introduction Polyfunctional organometallics are useful reagentsfor the preparation of awide range of complex molecules, and there- fore play an important role in modernorganic chemistry.[1] In the past decades,several preparationmethods of these re- agents have been disclosedand the development of various [1,2,3] halogen–metal exchange reagentshave been reported. Al- Scheme1.Br/Zn exchange on dibromoalkenes. kyllithium reagents (nBuLi, sBuLi, or tBuLi),[4] for example, pro- mote efficient iodine or bromine–lithium exchange reactions, whereas the “turbo-Grignard” iPrMgCl·LiClhas been used to Also, dibromoalkanes 8 and 9 are suitable substrates for bro- prepareaplethora of magnesium organometallics.[5] However, mine–zinc exchange reactions using triorganozincates lithium and magnesium reagents are highly reactive and there- (Scheme 2). Thus, when being treated with nBu3ZnLi (3)or fore often lack sensitive functional group tolerance, like nitro, sBu3ZnLi (10), an initial Br/Zn exchange leads to alkylzincs 11– azido, or triazine groups,orfunctionalities bearing acidic pro- 12,which,after rearrangement, provides dialkylzinc re- tons. Hence, zinc organometallic reagents have been devel- agents 13–14.After acylation or palladium-catalyzed Negishi oped to perform efficient and yet mild halogen–zincexchange cross-coupling[7] the functionalized alkanes 15–16 are obtained reactions. In this Minireview,recent advances of the halogen– in 62–75 %yield (Scheme2).[8] zinc exchange are described, with aspecial focus on novel acti- vated dialkylzinc exchange reagents. Halogen–Zinc Exchange Using Tri- or Tetra- alkylzincates (R3ZnLi or R4ZnLi2) Efficient reagents for halogen–zincexchange reactions are tri- organo-(R3ZnLi, R=alkyl) or tetraorganozincates (R4ZnLi2) which are preparedbymixingadialkylzinc with variousequiv- alents of an organolithium RLi.[2] Thus, when dibromoalkenes Scheme2.Br/Zn exchange on dibromoalkanes, followed by intramolecular of type 1 or 2 are treated withtriorganozincate nBu3ZnLi (3, alkylation and electrophilic quenching. 1.2 equiv) in THF at 858Cfor 3h,abromine–zinc exchange À takes place, leading to alkenylzinc reagents 4 and 5.After hy- drolysis, monobromoalkenes 6 and 7 are obtained in 82–97% An originalapproachtowards benzylic zinc reagents was yield (Scheme 1).[6] found, when iodoarene 17 is treated with nBu3ZnLi (3)or [a] Dr.M.Balkenhohl, Prof. Dr.P.Knochel tBu3ZnLi (18,Scheme 3). An I/Zn exchange takes place readily Department Chemie und Pharmazie at 858C, producing organozincs 19–20,which,after warming À Ludwig-Maximilians-UniversitätMünchen to 408C, undergo intramolecular alkylation,leadingtoben- À Butenandtstrasse5–13, Haus F, 81377 München (Germany) zylic zinc reagents 21–22.After quenching with aldehydes,al- E-mail:[email protected] cohols 23–24 are obtained in 56–80 %yield (Scheme 3).[9] The ORCID identification number(s) for the author(s) of this articlecan be found under: The high reactivity of lithium zincates allows the per- https://doi.org/10.1002/chem.201904794. formance of I/Zn exchange reactions on iodoarenes as dis- 2019 The Authors. Published by Wiley-VCH Verlag GmbH&Co. KGaA. closed by Sakamotoand Kondo (Scheme 4).[10] Thus, sensitive This is an open access article under the terms of Creative Commons Attri- iodoarenes 25–26 bearing an ester andanitro group are treat- bution NonCommercial-NoDerivs License, which permits use and distribu- ed with Me3ZnLi (27)at 78 8Cfor 1h,providing the lithium tion in any medium, provided the originalwork is properly cited, the use is [10] À non-commercial and no modifications or adaptations are made. arylzincates 28–29. After reactionwith benzaldehyde,alco- Selected by the EditorialOffice for our Showcaseofoutstanding Review- hols 30–31 are obtained in 68–74 %yield. Also, tBu3ZnLi (18) type articles (www.chemeurj.org/showcase). reacts readily with an electron-rich aryl iodide 32,providing Chem. Eur.J.2020, 26,3688 –3697 www.chemeurj.org 3689 2019 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Minireview Structural and reactivity insights on magnesium zincates were reported by Hevia and co-workers.[13] Thus, mixing tBuMgCl (3.0 equiv) with ZnCl2 (1.0 equiv) leads to the forma- tion of magnesium trialkylzincate 41.When aryl iodides 42–43 are treated with 41,the magnesium triarylzincates 44–45 are obtained and used in palladium-catalyzed cross-couplingreac- tions with aryl bromides, yieldingbiaryls 46–47 in 75–86 % yield (Scheme 6).[13] Scheme3.I/Zn exchange on aryl halides bearingaremote mesylate leaving group,affording benzylic zinc reagents after intramolecular alkylation. Scheme6.I/Zn exchange using amagnesium triorgano zincatefollowed by cross-coupling reactions. Moritz Balkenhohl was born 1992 in Speyer (Germany). He studied chemistryatthe Julius- Maximilians-UniversitätWürzburg and at Im- perialCollege London. In2015hejoined the groupofProf. Paul Knochel for his Master Scheme4.I/Zn exchange on aryl iodides bearing sensitive electrophilic func- thesisinMunich and started his PhD thesisin tional groups as well as an I/Zn exchange on 2-iodoanisole. 2016. After having finishedhis PhD in 2019, he remainedinthe laboratory of Prof. Kno- chel as apostdoctoral researcher,and will now join the groupofProf. Erick M. Carreira the zincate 33,which leads to 34 after quenching with benzal- at the ETH Zürichfor his postdoctoralplace- dehydein83% yield (Scheme 4).[11] ment. His research focuses on the functionali- zationofchallenging heterocycles, and halo- Also, protected indoles(35–36)are suitable for such an ex- gen–metalexchange reactions. change (Scheme 5).[12] Interestingly,the yield is increased by Paul Knochel was born 1955 in Strasbourg 10%byadding one equivalent of TMEDA (tetramethylethyle- (France). He studied at the University of Stras- nediamine) to Me3ZnLi (27). After halogen–metalexchange, bourg(France)and did his PhD at the ETH the zincates 37–38 are quenched with benzaldehyde or allyl Zürich(D. Seebach). He spent 4years at the bromide, giving rise to functionalized indoles 39–40 in 61– University Pierre and Marie Curie in Paris (J.-F. Normant) and one year at Princeton Universi- 64%yield (Scheme 5).[12] ty (M. F. Semmelhack). In 1987,hewas ap- pointed Professor at the University of Michi- gan. In 1992, he moved to Philipps-University at Marburg (Germany). In 1999, he then moved to the Chemistry Departmentof Ludwig-Maximilians-University in Munich (Germany). His research interests includethe development of novel organometallic re- agents and methods for use in organic synthesis,asymmetric catalysisand nat- ural product synthesis. Prof. Knochel received many distinguished prices as for example, the BerthelotMedalofthe Academie des Sciences (Paris), the IUPAC ThiemePrize, the Otto-Bayer-Prize, the Leibniz-Prize, the Arthur C. Cope Scholar Award, Karl-Ziegler-Prize, the NagoyaGold Medal, the H. C. Brown Award and Paul Karrer gold medal. He is member of the AcadØmie des Sciences,the Bavar- ian AcademyofScience,the German Academy of Sciences Leopodina. He is author of over 900 publications. Scheme5.I/Zn exchange reactionsonindoles, using Me3ZnLi·TMEDA. Chem. Eur.J.2020, 26,3688 –3697 www.chemeurj.org 3690 2019 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Minireview To improvethe utility and scope of these zincates,higher These methodologies were extended to N-heterocycles [14] [16] order reagents of type R4ZnLi2 were developed. In this way, (Scheme 9). The more reactive zincate nBu4ZnLi2·TMEDA (60) non-activated substrates such as bromobenzene (48)are zin- is used to convert various bromo-pyridines and -quinolines cated using the reagent Me ZnLi (49, 20 8C, 2h)and, after (61–64)tothe corresponding lithium zincates.After quenching 4 2 À quenching with benzaldehyde, alcohol 50 is obtained in 47% with iodine, diphenyl disulfide or 5-bromopyrimidine in the [14] yield (Scheme 7). When Me3ZnLi (27) is used as exchange re- presence of apalladium catalyst, the functionalized pyri- agent, no halogen–metal exchange takes place. Additionally, dines 65–68 are obtained in 40–75 %yield.[16] Remarkably,the the resultingzincate speciesproves to be more reactive to- halogen–zinc exchange is performed in toluene and substoi- wards electrophilicquenchreactions. When aryl iodide 51,for chiometric exchange reagent (0.33 equiv) is used, demonstrat- example, is treated with Me3ZnLi (27), merely an iodine–zinc ing that three of the four alkyl groups participate in this ex- exchange is observed. However,when 51 is treated with the change reaction.[16] higher order zincate 49,anintramolecularMichael addition proceeds after the exchange reaction, providing the indo- line