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.
This Minireview describes the scope of the halogen–magnesium exchange. It shows that the use of the turbo‐Grignard reagent (iPrMgCl⋅LiCl) greatly enhances the rate of the Br– and I–Mg exchange. ...Furthermore, this magnesium reagent allows the performance of a fast sulfoxide–magnesium exchange. Also, the use of sBuMgOR⋅LiOR (R=2‐ethylhexyl) enables a Br–Mg exchange in toluene leading to various Grignard reagents in toluene. Additionally, the new exchange reagent sBu2Mg⋅2 LiOR (R=2‐ethylhexyl) further increases the rate of the halogen–magnesium exchange allowing one to perform a chlorine–magnesium exchange for aromatic chlorides bearing an ortho‐methoxy substituent in toluene.
Go go gadget Grignard! This Minireview describes the rational development of more effective halogen–magnesium exchange reagents, culminating with the elaboration of magnesium reagents allowing the performance of such exchanges in non‐polar non‐ethereal solvents and allowing a chlorine–magnesium exchange to take place under mild conditions with several aryl chlorides.
The preparation of highly functionalized organometallic compounds can be achieved by direct CH activation of a broad range of unsaturated substrates using lithium chloride solubilized ...2,2,6,6‐tetramethylpiperidide bases (TMPnMXm⋅p LiCl). These are excellent reagents for converting a wide range of aromatic and heterocyclic substrates into valuable organometallic reagents with broad applications in organic synthesis.
Valuable synthetic intermediates can be obtained by quenching with various electrophiles highly functionalized aryl‐, heteroaryl‐, and alkenylmetal compounds prepared by direct CH activation using lithium chloride solubilized 2,2,6,6‐tetramethylpiperidide bases, such as TMPMgCl⋅LiCl, TMPZnCl⋅LiCl, or TMP2Zn⋅2 LiCl, which tolerate a wide range of functional groups. The scope and limitations are given for each LiCl‐solubilized base.
We report a range of highly regioselective openings of 1.1.1propellane with various allylic zinc halides, as well as zinc enolates of ketones, esters and nitriles. The resulting zincated ...bicyclopentanes (BCPs) were trapped with a range of electrophiles including acyl chlorides, sulfonothioates, hydroxylamino benzoates, tosyl cyanide as well as aryl and allyl halides, generating highly functionalized BCP‐derivatives. The unusually high regioselectivity of these reactions has been rationalized using DFT calculations. A bioisostere of the synthetic opioid pethidine was prepared in 95 % yield in one step using this method.
A wide range of allylic zinc reagents as well as zinc enolates open 1.1.1propellane to generate zincated bicyclopentanes (BCPs) in a highly regioselective manner. These intermediate zinc reagents are trapped with various electrophiles, giving access to fully functionalized BCPs including a BCP‐analogue of the synthetic opioid pethidine.
A formal regioselective cross-coupling of various pyridines with alkyl and aryl groups can be achieved by a BF3·OEt2-mediated addition of Grignard or organozinc reagents to pyridines bearing various ...substituents (chloro, bromo, cyano, vinyl, phenyl, carbethoxy, nitro, etc.) followed by an oxidative aromatization mediated by chloranil. Good regioselectivity and wide functional group tolerance make this method very versatile for the preparation of polyfunctional pyridines. No transition-metal catalyst is required in these coupling reactions.
A wide range of aryl and heteroaryl bromides, which are usually sluggish in exchange reactions, are readily converted into the corresponding Grignard reagents by means of a Br/Mg exchange reaction ...triggered by iPrMgCl⋅LiCl (see scheme). These Grignard intermediates react with electrophiles in good yields.
The first sodiations of (hetero)arenes in continuous flow using NaDA (sodium diisopropylamide) in Me2EtN are reported. This flow procedure enables sodiation of functionalized arenes and heteroarenes ...that decompose under batch‐sodiation conditions. The resulting sodiated (hetero)arenes react instantly with various electrophiles, such as ketones, aldehydes, isocyanates, alkyl bromides, and disulfides, affording polyfunctionalized (hetero)arenes in high yields. Scale‐up is possible without further optimization.
Taming sodium: Arenes and heteroarenes can be sodiated under flow conditions by using the soluble base sodium diisopropylamide (NaDA). This procedure is suitable for (hetero)arenes containing sensitive functional groups that decompose under batch‐sodiation conditions. The resulting sodiated (hetero)arenes react instantly with various electrophiles to yield polyfunctionalized (hetero)arenes in high yields.
Palladium, radically different: A wide range of polyfunctional aryl‐ and heteroarylmagnesium reagents undergo fast Kumada cross‐couplings (see scheme) with functionalized aryl bromides in the ...presence of a palladium catalyst and an alkyl iodide as additive. These reactions proceed by a radical pathway.
We report a general preparation of arylated bicyclo1.1.1pentanes through the opening of 1.1.1propellane with various arylmagnesium halides. After transmetalation with ZnCl2 and Negishi cross‐coupling ...with aryl and heteroaryl halides, bis‐arylated bicyclo1.1.1pentanes are obtained. These bis‐arylated bicyclo1.1.1pentanes may be considered as bioisosteres of internal alkynes. Bioisosteres of tazarotene and the metabotropic glutamate receptor 5 (mGluR5) antagonist 2‐methyl‐6‐(phenylethynyl)pyridine were prepared and their physicochemical properties were evaluated.
BCPs have the right profile! The opening of 1.1.1propellane with various arylmagnesium halides proceeds smoothly in sealed tubes to provide bicyclo1.1.1pentylmagnesium (BCP magnesium) derivatives. After transmetalation with ZnCl2, these undergo Negishi cross‐coupling with various aryl and heteroaryl halides to provide bis‐arylated BCPs, which represent a useful class of bioisosteres of alkynes or 1,4‐disubstituted arenes.
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