Recent Advances of the Halogen–Zinc Exchange Reaction

Abstract

For the preparation of zinc organometallics bearing highly sensitive functional groups such as ketones, aldehydes or nitro groups, especially mild halogen–zinc exchange reagents have proven to be of great potential. In this Minireview, the latest research in the area of the halogen–zinc exchange reaction is reported, with a special focus lying on novel dialkylzinc reagents complexed with lithium alkoxides. Additionally, the preparation and application of organofluorine zinc reagents and transition‐metal‐catalyzed halogen–zinc exchange reactions are reviewed.

A powerful exchange: Due to mild and yet reactive halogen–zinc exchange reagents, a plethora of highly functionalized sensitive zinc organometallics can be prepared. In this Minireview, the development of the halogen–zinc exchange reaction is explored, including the preparation and application of organofluorine zinc reagents. Also, extremely reactive dialkylzinc reagents complexed with lithium alkoxides are highlighted.

Introduction

Polyfunctional organometallics are useful reagents for the preparation of a wide range of complex molecules, and therefore play an important role in modern organic chemistry.1 In the past decades, several preparation methods of these reagents have been disclosed and the development of various halogen–metal exchange reagents have been reported.1, 2, 3 Alkyllithium reagents (nBuLi, sBuLi, or tBuLi),4 for example, promote efficient iodine or bromine–lithium exchange reactions, whereas the “turbo‐Grignard” iPrMgCl⋅LiCl has been used to prepare a plethora of magnesium organometallics.5 However, lithium and magnesium reagents are highly reactive and therefore often lack sensitive functional group tolerance, like nitro, azido, or triazine groups, or functionalities bearing acidic protons. Hence, zinc organometallic reagents have been developed to perform efficient and yet mild halogen–zinc exchange reactions. In this Minireview, recent advances of the halogen–zinc exchange are described, with a special focus on novel activated dialkylzinc exchange reagents.

Halogen–Zinc Exchange Using Tri‐ or Tetraalkylzincates (R₃ZnLi or R₄ZnLi₂)

Efficient reagents for halogen–zinc exchange reactions are triorgano‐ (R₃ZnLi, R=alkyl) or tetraorganozincates (R₄ZnLi₂) which are prepared by mixing a dialkylzinc with various equivalents of an organolithium RLi.2 Thus, when dibromoalkenes of type 1 or 2 are treated with triorganozincate nBu₃ZnLi (3, 1.2 equiv) in THF at −85 °C for 3 h, a bromine–zinc exchange takes place, leading to alkenylzinc reagents 4 and 5. After hydrolysis, monobromoalkenes 6 and 7 are obtained in 82–97 % yield (Scheme 1).6

Scheme 1.

Br/Zn exchange on dibromoalkenes.

Also, dibromoalkanes 8 and 9 are suitable substrates for bromine–zinc exchange reactions using triorganozincates (Scheme 2). Thus, when being treated with nBu₃ZnLi (3) or sBu₃ZnLi (10), an initial Br/Zn exchange leads to alkylzincs 11–12, which, after rearrangement, provides dialkylzinc reagents 13–14. After acylation or palladium‐catalyzed Negishi cross‐coupling7 the functionalized alkanes 15–16 are obtained in 62–75 % yield (Scheme 2).8

Scheme 2.

Br/Zn exchange on dibromoalkanes, followed by intramolecular alkylation and electrophilic quenching.

An original approach towards benzylic zinc reagents was found, when iodoarene 17 is treated with nBu₃ZnLi (3) or tBu₃ZnLi (18, Scheme 3). An I/Zn exchange takes place readily at −85 °C, producing organozincs 19–20, which, after warming to −40 °C, undergo intramolecular alkylation, leading to benzylic zinc reagents 21–22. After quenching with aldehydes, alcohols 23–24 are obtained in 56–80 % yield (Scheme 3).9

Scheme 3.

I/Zn exchange on aryl halides bearing a remote mesylate leaving group, affording benzylic zinc reagents after intramolecular alkylation.

The high reactivity of lithium zincates allows the performance of I/Zn exchange reactions on iodoarenes as disclosed by Sakamoto and Kondo (Scheme 4).10 Thus, sensitive iodoarenes 25–26 bearing an ester and a nitro group are treated with Me₃ZnLi (27) at −78 °C for 1 h, providing the lithium arylzincates 28–29.10 After reaction with benzaldehyde, alcohols 30–31 are obtained in 68–74 % yield. Also, tBu₃ZnLi (18) reacts readily with an electron‐rich aryl iodide 32, providing the zincate 33, which leads to 34 after quenching with benzaldehyde in 83 % yield (Scheme 4).11

Scheme 4.

I/Zn exchange on aryl iodides bearing sensitive electrophilic functional groups as well as an I/Zn exchange on 2‐iodoanisole.

Also, protected indoles (35–36) are suitable for such an exchange (Scheme 5).12 Interestingly, the yield is increased by 10 % by adding one equivalent of TMEDA (tetramethylethylenediamine) to Me₃ZnLi (27). After halogen–metal exchange, the zincates 37–38 are quenched with benzaldehyde or allyl bromide, giving rise to functionalized indoles 39–40 in 61–64 % yield (Scheme 5).12

Scheme 5.

I/Zn exchange reactions on indoles, using Me₃ZnLi⋅TMEDA.

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 formation 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‐coupling reactions with aryl bromides, yielding biaryls 46–47 in 75–86 % yield (Scheme 6).13

Scheme 6.

I/Zn exchange using a magnesium triorgano zincate followed by cross‐coupling reactions.

To improve the utility and scope of these zincates, higher order reagents of type R₄ZnLi₂ were developed.14 In this way, non‐activated substrates such as bromobenzene (48) are zincated using the reagent Me₄ZnLi₂ (49, −20 °C, 2 h) and, after quenching with benzaldehyde, alcohol 50 is obtained in 47 % yield (Scheme 7).14 When Me₃ZnLi (27) is used as exchange reagent, no halogen–metal exchange takes place. Additionally, the resulting zincate species proves to be more reactive towards electrophilic quench reactions. When aryl iodide 51, for example, is treated with Me₃ZnLi (27), merely an iodine–zinc exchange is observed. However, when 51 is treated with the higher order zincate 49, an intramolecular Michael addition proceeds after the exchange reaction, providing the indoline 52 in 66 % yield (Scheme 7).14

Scheme 7.

Halogen–zinc exchange using the higher order zincate Me₄ZnLi₂ (49).

Interestingly, highly reactive zincates of type R₄ZnLi₂ remain fairly functional group tolerant and allow smooth halogen–zinc exchange reactions in the presence of for example, an amide or a chiral acetal (Scheme 8).15 When iodoarene 53 is treated with tBu₄ZnLi₂ (54, 1.1 equiv), an iodine–zinc exchange readily proceeds. After allylation, the chiral product 55 is isolated in 74 % yield and 99 % ee. Amide 56 is allylated under similar conditions, leading to the allylated product 57 in 87 % yield. Remarkably, the exchange is also possible with 4‐iodophenol (58), if an excess of 54 is used (2.2 equiv), which leads, after allylation, to phenol 59 in 79 % yield (Scheme 8).15

Scheme 8.

Halogen–zinc exchange of sensitive aryl halides and of an unprotected phenol.

These methodologies were extended to N‐heterocycles (Scheme 9).16 The more reactive zincate nBu₄ZnLi₂⋅TMEDA (60) is used to convert various bromo‐pyridines and ‐quinolines (61–64) to the corresponding lithium zincates. After quenching with iodine, diphenyl disulfide or 5‐bromopyrimidine in the presence of a palladium catalyst, the functionalized pyridines 65–68 are obtained in 40–75 % yield.16 Remarkably, the halogen–zinc exchange is performed in toluene and substoichiometric exchange reagent (0.33 equiv) is used, demonstrating that three of the four alkyl groups participate in this exchange reaction .16

Scheme 9.

Bromine–zinc exchange on various bromo‐pyridines and ‐quinolines using nBu₄ZnLi₂⋅TMEDA (60).

Additionally, zincate reagents are used for the generation of benzynes, which subsequently undergo facile Diels–Alder cycloaddition reactions.17 Also, zincates may participate in oxovanadium(V)‐induced cross‐coupling reactions.18 2‐Thienyl zincates are used in the preparation of poly(3‐hexylthiophene) (P3HT), which belongs to the class of poly‐alkylthiophenes; PATs, that are of interest as organic materials.19

Halogen–Zinc Exchange Using Dialkylzincs

Early studies towards halogen–zinc exchange reactions were reported by Nishimura and Hashimoto for the preparation of zinc carbenoids.20 Tetramethylethylene, for example, is treated with diethylzinc and diiodomethane, which leads to the cyclopropanated product in 53 % yield.20a In contrast to the well‐known Simmons–Smith reaction,21 which requires 15–70 h reaction time, this cyclopropanation proceeds within minutes. A broader substrate scope is achieved, when functionalized alkyl iodides are added to Et₂Zn (5.0 equiv, neat) and stirred at elevated temperatures.22 Thus, alkyl iodide 69, bearing an ester functional group, is mixed with Et₂Zn (70, 5.0 equiv) and stirred at 50 °C for 4 h, which gives the mixed zinc species 71. After removal of the volatiles (Et₂Zn, EtI), dialkylzinc 72 is obtained, which undergoes a Michael‐addition to a nitroolefin, producing the functionalized alkane 73 in 82 % yield (Scheme 10). Zinc organometallics obtained by the same22 or a similar23 method (74–75) are also used for asymmetric addition reactions in the presence of the chiral catalyst 76. The resulting dialkylzincs are treated with aldehydes, leading to the chiral alcohols 77–78 in 88–95 % yield and up to 93 % ee (Scheme 10).22, 23 Notably, 78 is a prostaglandin and leukotriene building block.23a

Scheme 10.

Generation of alkylzincs using diethylzinc and their trapping reactions.

The iodine–zinc exchange of secondary alkyl iodides 79 proceeds using iPr₂Zn (80).24 Remarkably, when the reagent is prepared from 2 iPrMgBr and ZnBr₂, leading to iPr₂Zn⋅2MgBr₂ (81), the exchange reaction proceeds up to 200 times faster due to the presence of this magnesium salt.24 This may be explained by the formation of the dibromozincate [iPr₂ZnBr₂]²⁻[Mg₂Br₂]²⁺. Thus, when secondary iodides (79 a–b) are treated with iPr₂Zn (80, 1.5 equiv), the alkylzinc reagents 82 a–b are obtained (Scheme 11). After transmetallation to copper using a CuCN⋅2LiCl solution in THF and electrophilic trapping, alkyne 83 and ketone 84 are obtained in 62–82 % yield.

Scheme 11.

Iodine–zinc exchanges of secondary alkyl iodides using iPr₂Zn (80) or iPr₂Zn⋅2MgBr₂ (81).

Menthyl iodide (79 c) is used for this transformation, which, after mixing with iPr₂Zn⋅2MgBr₂ (81), gives the mixed zinc organometallic 82 c. After copper‐mediated allylation, the cyclohexane 85 is isolated in 61 % yield (Scheme 11).24

After the discovery, that salt additives may accelerate the rate of iodine–zinc exchange reactions,24 it was found that the combination of iPr₂Zn (80) and Li(acac) (10 mol %) in Et₂O:NMP allowed efficient halogen–zinc exchange reactions on aryl iodides.25 Thus, various aryl iodides bearing sensitive functional groups such as isothiocyanates or aldehydes of type 86 are treated with iPr₂Zn (80) and catalytic amounts of Li(acac) (10 mol %), generating biarylzincs of type 87. Trapping with various electrophiles gives 88 a–c in 60–84 % yield (Scheme 12).25 From a mechanistic perspective, the acetylacetonate anion may lead to the formation of a tetracoordinated zinc species. This intermediate A is reactive enough to undergo a second iodine–zinc exchange, providing zincate B, which leads to diarylzinc 87 and Li(acac) (Scheme 12).25

Scheme 12.

Preparation of highly functionalized diarylzincs using iPr₂Zn in the presence of catalytic amounts of Li(acac).

Various additives play a major role in the rates of halogen–metal exchange reactions (e.g. LiCl,5 MgBr₂,24 or Li(acac)25). In most cases, it is presumed that the additive leads to the formation of a higher coordinated zincate and thus more reactive metal intermediate. In the course of our investigations towards the preparation of more efficient halogen–magnesium exchange reagents, it was found that the addition of alcoholates may drastically increase the reactivity of the halogen–magnesium exchange.26 With this information at hand, the generation of dialkylzinc organometallics, complexed with lithium alkoxides were investigated.27 When an aminoalcohol ROH (89, 2.0 equiv, R=CH₂CH₂N‐(CH₃)CH₂CH₂N(CH₃)₂),) is treated with Et₂Zn in toluene, a mixed zinc species, tentatively described as [ROZnEt⋅ROH] (90) is obtained.

Upon addition of sBuLi (2.0 equiv), di‐sec‐butylzinc complexed with two lithium alkoxides of the formula sBu₂Zn⋅2LiOR (91) is produced (Scheme 13).27

Scheme 13.

Preparation of the dialkylzinc reagent sBu₂Zn⋅2LiOR (91).

This exchange reagent is highly reactive towards iodine or bromine–zinc exchange reactions. Indeed, the iodine–zinc exchange of 3‐iodoanisole (92) is complete after only 1 minute, providing the diarylzinc 93 (Scheme 14). After a palladium‐catalyzed Negishi cross‐coupling with an aryl iodide,7 biaryl 94 is isolated in 76 % yield. Similarly, a functionalized pyridine 95 or a pyridone derivative 96 are suitable substrates for this exchange reaction, leading to zinc organometallics 97–98. After copper‐mediated acylation or allylation, ketone 99 and lactam 100 are obtained in 85–96 % yield (Scheme 14).27

Scheme 14.

Generation of diarylzinc organometallics using sBu₂Zn⋅2LiOR (91).

Since zinc organometallics possess a particularly unreactive carbon–zinc bond, highly sensitive functional groups such as triazines, aldehydes, ketones or nitro‐groups are tolerated. Under standard reaction conditions, an aryl iodide bearing a triazine functional group (101 a) is converted to the diarylzinc 102 a and quenched with allyl bromide, providing 103 a in 72 % yield (Scheme 15).27 In some cases, slight modifications of the exchange reagent are required. Thus, when 2,4‐dinitroiodobenzene (101 b) is treated with pTol₂Zn⋅2LiOR (104, 0.6 equiv, −15 °C, 15 min), a smooth iodine–zinc exchange takes place, affording 102 b, which, after allylation, leads to the dinitroarene 103 b in 79 % yield. For an iodine–zinc exchange to proceed in the presence of aldehydes, tBu₂Zn⋅2LiOR (105) gives the best results. Hence, 5‐iodo‐2‐furaldehyde (101 c) is treated with the exchange reagent 105 (0.8 equiv, 0 °C, 10 min), leading to biarylzinc 102 c. After an allylation, the furyl aldehyde 103 c is obtained in 66 % yield (Scheme 15).27

Scheme 15.

Iodine–zinc exchange of highly sensitive substrates using exchange reagents of the general formula R₂Zn⋅2LiOR. [a] CuI (20 mol%) is used. [b] sBu₂Zn⋅2LiOR (91, 0.6 equiv, 25 °C, 10 min). [c] pTol₂Zn⋅2LiOR (104, 0.6 equiv, –15 °C, 15 min) is used. [d] tBu₂Zn⋅2LiOR (105, 0.8 equiv, 0 °C, 10 min) is used.

Finally, the high reactivity of these alkoxide complexed dialkylzinc reagents allow a bromine–zinc exchange reaction. Therefore, various functionalized (hetero)aryl bromides (106 a–d) are treated with 91 (0.8 equiv, 25 °C, 30 min–5 h), producing biarylzincs 107 a–d. After various electrophilic trapping reactions, a plethora of functionalized arenes and heteroarenes 108 a–d are obtained in 60–77 % yield (Scheme 16).27

Scheme 16.

Bromine–zinc exchange of various (hetero)aryl bromides using sBu₂Zn⋅2LiOR (91). [a] Pd(OAc)₂ (3 mol%), SPhos (6 mol%) and TMSCl (0.8 equiv) are used. [b] A 1 m CuCN⋅2LiCl solution in THF is used (20 mol%). [c] CuI (20 mol%) is used.

Transition‐Metal‐Catalyzed Halogen–Zinc Exchange Reactions

The addition of transition metal salts also catalyzed the halogen–zinc exchange. Whereas without a transition metal a large excess of Et₂Zn (5.0 equiv) is required to perform an iodine–zinc exchange,22 the addition of CuI (0.3 mol %) reduces the amount to 1.5 equivalents. Also, the rate of the exchange reaction is doubled.28 Alkyl iodide 109, for example, when being treated with Et₂Zn (1.5 equiv) in the presence of CuI (0.3 mol %) and stirred at 50–55 °C for 8 h, undergoes a complete exchange. The resulting dialkylzinc 110 enantioselectively adds to an aldehyde in the presence of the chiral catalyst 76 (8 mol %), providing the alcohol 111 in 68 % yield and 95 % ee (Scheme 17).28 It is noteworthy that the iodine–metal exchange is incomplete in absence of the copper salt and only a yield of 33 % is obtained. When MnBr₂ (5 mol %) and CuCl (0.3 mol %) are simultaneously present in the reaction mixture, not only alkyl iodides but also alkyl bromides readily undergo halogen–metal exchange reactions.29 Thus, when 4‐bromobutyrate (112) is treated with Et₂Zn (0.9 equiv), MnBr₂ (5 mol %), and CuCl (0.3 mol %), alkylzinc bromide 113 is obtained. A subsequent palladium‐catalyzed cross‐coupling, provides the 1,2‐functionalized arene 114 in 71 % yield (Scheme 17).

Scheme 17.

Copper‐ and manganese‐catalyzed halogen–zinc exchange reactions.

Various transition metals are able to catalyze an I/Zn exchange and palladium(II) or nickel(II) salts are suitable additives to increase the rate of iodine–zinc exchange reactions.30 When iodoalkane 115, which contains a remote alkene moiety, is treated with Et₂Zn (2.0 equiv) in the presence of PdCl₂(dppf) (1.5 mol %) an iodine–zinc exchange takes place, followed by cyclization, which leads to an organozinc halide 116. A copper‐mediated substitution reaction produces the functionalized cyclopentane 117 in 80 % yield (Scheme 18).30 From a mechanistic perspective, it is presumed that palladium undergoes an oxidative addition to the carbon iodine bond, followed by intramolecular carbopalladation. After two ligand exchange reactions, 116 is formed, ethane and ethylene are set free, and the Pd⁰ species is regenerated (Scheme 18).30

Scheme 18.

Palladium catalyzed iodine–zinc exchange reactions, leading to functionalized cyclopentanes.

Such cyclization reactions are highly stereoselective and the ring closure of iodoalkane 118, when treated with Et₂Zn in the presence of the palladium catalyst, produces, after an iodine–zinc exchange and copper‐mediated allylation, the trisubstituted cyclopentane 119 in a stereoconvergent manner (Scheme 19).30b

Scheme 19.

Stereoselective preparation of a trisubstituted cyclopentane by radical cyclization after iodine–zinc exchange.

Nickel‐catalysis proved to be beneficial for the stereoselective preparation of heterocyclic zinc reagents.^30d Thus, when the iodinated acetal 120 is treated with Et₂Zn (2.0 equiv) in the presence of Ni(acac)₂ (2 mol %) the radical intermediate 121 forms, which cyclizes to the alkylzinc iodide 122. Transmetalation to copper and trapping with ethyl propiolate provides tetrahydrofuran 123 in 63 % yield and a cis:trans selectivity of 15:85 (Scheme 20).30d

Scheme 20.

Nickel‐catalyzed iodine–zinc exchange for the stereoselective preparation of tetrahydrofuran derivatives.

When the iodo‐tetrahydrofuran 124 is used under the same reaction conditions, an iodine–zinc exchange leads to the most stable radical 125, in which the alkyl substituents at C1 and C2 are in equatorial position and the alkoxy substituent (C3) is positioned axially. After reaction with benzoyl chloride, the bicyclic heterocycle 126 is isolated in 64 % yield (exo:endo=2:98, Scheme 21).^30d

Scheme 21.

Stereoselective cyclization of an iodo‐tetrahydrofuran using a nickel‐catalyzed iodine–zinc exchange.

A further extension is achieved, when electron‐rich triorganozincates are combined with iron or cobalt catalysts, which enables chlorine–zinc exchange reactions.31 Adamantyl chloride (127), for example, is treated with the zincate 128 in the presence of Fe(acac)₂ (10 mol %) and 4‐fluorostyrene (20 mol %). After quenching of the resulting metal species with MeSO₂SMe, the thioether 129 is obtained in 66 % yield (Scheme 22).31 To expand the scope of this exchange reaction, the zincate 130 was developed. However, the catalytic system needs to be modified and Co(acac)₂ provides best results. Thus, trichlorinated arene 131 is treated with 130 in the presence of Co(acac)₂ (20 mol %) and 4‐fluorostyrene (50 mol %) at elevated temperatures (50 °C, 5 h). Quenching of the resulting organometallic with PhSO₂SPh produces the diarylthioether 132 in 63 % yield (Scheme 22).31

Scheme 22.

Iron‐ and cobalt‐catalyzed chlorine–zinc exchange reactions using electron‐rich triorganozincates.

Generation of Fluorinated Organozinc Reagents by Halogen–Zinc Exchange Reactions

It was found, that fluorinated iodoalkanes react with diethylzinc in the presence of a Lewis‐base, producing dialkylzinc reagents.32 A synthetic utility for these fluorinated zinc organometallics was introduced by reacting these reagents with diiodo(hetero)arenes under copper catalysis, producing fused fluorinated ring systems.33 Building up on these results, a dialkylzinc reagent, designed for difluoromethylation reactions, was developed.34 Thus, when difluoroiodomethane is treated with Et₂Zn (0.5 equiv) in DMPU (N, N′‐dimethylpropyleneurea), the zinc reagent 133 is obtained in 94 % yield. Mixing 133 with aryl halides or triflates, such as 134–135, under nickel‐catalysis in DMSO, affords the difluoromethylated (hetero)arenes 136–137 in 67–72 % yield (Scheme 23).34

Scheme 23.

Preparation of the difluoromethylation reagent 133 by iodine–zinc exchange reaction and further cross‐coupling reactions.

An interesting example for a difluoromethylene bis‐carbanion surrogate is accessible by a cobalt‐catalyzed halogen–zinc exchange reaction.35 Thus, when (bromodifluoromethyl)‐trimethylsilane (Me₃SiCF₂Br, 138) is treated with iPrZnI (1.0 equiv, 5 °C, 20 h) in the presence of CoBr₂⋅dppe (1 mol %), the fluorinated alkylzinc organometallic 139 is generated in 88 % yield. It should be noticed, that a reductive zinc insertion reaction mainly leads to homo‐coupling of the zinc species. In the first step, the generated alkylzinc 139 undergoes a copper‐catalyzed allylation reaction, providing intermediate 140 in 80 % yield. Next, the silyl group is activated by catalytic amounts of cesium fluoride (15 mol %) and mixed with 4‐chlorobenzaldehyde, producing alcohol 141 in 98 % yield (Scheme 24).35

Scheme 24.

Preparation of geminal difluoro derivatives by a bromine–zinc exchange.

An example for the preparation of in situ generated fluorinated alkylzinc organometallics by iodine–zinc exchange is described by Uchiyama and Hirano.36 Various fluorinated halogenated arenes and alkenes (142, 2.25 equiv) are mixed with iodoarenes of type 143, and Et₂Zn (1.5 equiv), copper iodide (10 mol %), and phenanthroline (0–20 mol %) are added. After stirring at 90 °C for 16 h, the cross‐coupled products 144 a–d are obtained in 56–88 % yield (Scheme 25).36

Scheme 25.

Copper‐catalyzed cross‐coupling reactions of various fluorinated arenes and alkanes with aryl iodides.

Conclusion

The development of the halogen–zinc exchange reaction over the last decades has made considerable progress. The traditional approach to prepare alkylzinc organometallics by zinc insertion has been significantly extended with the development of new and highly reactive halogen–zinc exchange reagents. Both the use of lower order triorganozincates of type R₃ZnLi or higher order tetraorganozincates of type R₄ZnLi₂ allow the preparation of various functionalized organic molecules, especially since the resulting zinc species are highly reactive towards various electrophiles. A milder approach was developed by using a set of dialkylzinc reagents complexed with metallic salts such as MgBr₂, Li(acac), or lithium alkoxides. Especially dialkylzinc organometallics complexed with lithium alkoxides of type R₂Zn⋅2LiOR show a large increase in reactivity in comparison with previously developed halogen–zinc exchange reagents, enabling a bromine–zinc exchange reaction in both ethereal and non‐polar solvents. Also, a range of transition‐metal‐catalyzed halogen–zinc exchange reactions have been developed, which enable a chlorine–zinc exchange reaction. A large application field for the halogen–zinc exchange reaction has been found in the preparation of sensitive fluorinated organozinc reagents, which can be employed in difluoromethylation or cross‐coupling reactions. The latest developments towards the preparation of highly reactive and yet mild diorganozinc reagents will pave the way for novel transformations, relying on the optimal balance between increasing reactivity and high functional group tolerance.

Conflict of interest

The authors declare no conflict of interest.

Biographical Information

Moritz Balkenhohl was born 1992 in Speyer (Germany). He studied chemistry at the Julius‐Maximilians‐Universität Würzburg and at Imperial College London. In 2015 he joined the group of Prof. Paul Knochel for his Master thesis in Munich and started his PhD thesis in 2016. After having finished his PhD in 2019, he remained in the laboratory of Prof. Knochel as a postdoctoral researcher, and will now join the group of Prof. Erick M. Carreira at the ETH Zürich for his postdoctoral placement. His research focuses on the functionalization of challenging heterocycles, and halogen–metal exchange reactions.

Biographical Information

Paul Knochel was born 1955 in Strasbourg (France). He studied at the University of Strasbourg (France) and did his PhD at the ETH Zürich (D. Seebach). He spent 4 years at the University Pierre and Marie Curie in Paris (J.‐F. Normant) and one year at Princeton University (M. F. Semmelhack). In 1987, he was appointed Professor at the University of Michigan. In 1992, he moved to Philipps‐University at Marburg (Germany). In 1999, he then moved to the Chemistry Department of Ludwig‐Maximilians‐University in Munich (Germany). His research interests include the development of novel organometallic reagents and methods for use in organic synthesis, asymmetric catalysis and natural product synthesis. Prof. Knochel received many distinguished prices as for example, the Berthelot Medal of the Academie des Sciences (Paris), the IUPAC Thieme Prize, the Otto‐Bayer‐Prize, the Leibniz‐Prize, the Arthur C. Cope Scholar Award, Karl‐Ziegler‐Prize, the Nagoya Gold Medal, the H. C. Brown Award and Paul Karrer gold medal. He is member of the Académie des Sciences, the Bavarian Academy of Science, the German Academy of Sciences Leopodina. He is author of over 900 publications.

M. Balkenhohl, P. Knochel, Chem. Eur. J. 2020, 26, 3688.