A Ball‐Milling‐Enabled Reformatsky Reaction

Abstract An operationally simple one‐jar one‐step mechanochemical Reformatsky reaction using in situ generated organozinc intermediates under neat grinding conditions has been developed. Notable features of this reaction protocol are that it requires no solvent, no inert gases, and no pre‐activation of the bulk zinc source. The developed process is demonstrated to have good substrate scope (39–82 % yield) and is effective irrespective of the initial morphology of the zinc source.

Metal-mediated CÀCb ond formation is an essential tool in moderno rganic synthesis. Numerous reactions consistingo f metal-mediated nucleophilic addition to electrophiles have been developed for the synthesis of complex organic molecules. [1] However,t he generally high basicitya nd/or nucleophilicity of someo rganometallic reagents restricts their use in late-stage modification,w here sensitive functionalg roups may already exist in the chemical structure. Conversely,o rganozinc speciesr epresent ac lass of "mild" organometallicc ompounds that demonstrate excellent functional group compatibility. [2] Nevertheless, the preparation of organozinc species often requires initial access to more reactive organometallics, which are then transmetalated to give the desired organozincr eactant by metathesis with Zn II salts. Alternatively, activated Zn 0 can be used for the oxidative addition into carbon-halogen bonds (Scheme 1A). In generalt he formation and manipulation of organometallic compounds is not particularly clean or green when considering that solvents often have to be distilled and dried prior to use;i nert gases are commonly required, and, in the case of organozinc reagents, the form of the bulk metal can play an important role and chemical additives are typically required to generate the activated zinc species. [3] Recently,w ei dentified mechanochemistry and ball-milling as at ool for the straightforward generation of organozinc speciesw ithout the requirement for carefullyp repareds olvents or inert gases.U nder these conditions the input of mechanical energy is enough to break down the resilient metal oxide surface and, in the presenceo ft he alkyl/aryl halide,g enerate the corresponding organozinc species (Scheme 1B). [4] These organozinc speciesm ay then be intercepted by opening the grinding jar,a dding both catalyst and coupling partner beforet hen running at elescoped Negishic oupling reaction; such ap rocess is applicable to both sp 3 Àsp 3 ands p 3 Àsp 2 coupling reactions. We have exploited this concept to carry out the one-jar,o ne-step preparation andu se of organozinc species in ar obust mechanochemical Reformatsky reaction (Scheme 1C). The Reformatsky reactiono ffers excellent potential for the formation of CÀCb onds through (1) predictable CÀCf ormation, (2) neutralr eactionc onditions (in comparison to obtaining the same products through aldol condensation), (3) broad functional group tolerance, and (4) the ability to impart ah igh degree of stereocontrol. [5] The classical Reformatsky reaction, in which b-hydroxy esters are formed by the reaction of aldehydes/ketones with a-halo esters in the presence of metallicz inc, was reported in 1887. [6] Since this seminal work, av ariety of latent nucleophiles and electrophiles have been studied and applied in this reaction and it has been routinelyu sed in the synthesis of complex natural products. [7] However,t oc arry out the Reformatsky reaction, organozinc reagents must be prepareda tt he point of use;t he majority of organozinc reagents are not commercially available. [8] This process can be problematic, owing to the formationo falayer of passivating zinc oxide on the surface of zinc powder,w hichh ampers the formationo fo rganozinc species and requires removal through treatment with chemical additives. Such additives include aqueous acid, [9] iodine, [10] 1,2-di-Scheme1.A) Formation anduse of organzincr eagents. B) Previous work: one-jar two-step Negishi coupling. [4] C) This work:one-jar one-step mecha-nochemicalR eformatsky reaction. KGaA. This is an openaccessarticleunder the termsoft he Creative Commons AttributionL icense, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. bromoethane, [11] or chlorotrimethylsilane. [12] Highly reactive Rieke zinc is an alternative, but its preparation is nontrivial and requires the reduction of ZnCl 2 with alkali metals (Li, Na, K) and naphthalene. [13] Furthermore, the air-sensitivityo ft his methodr enders the green credentials of the Rieke approach poor,a nd the success of the outcome is highly dependento n the physicalf orm of zinc used. Multiple different forms of zinc are commercially available (see the Supporting Information; Figure S1). Therefore, the focus of this work is on the mechanical activation of zinc, which not only renders the process more operationally simple and cost effective, butalso delivers significant improvements to some of the green metrics typicallya ssociated with this reaction. [14] Mechanochemistry has been widely used among the crystal engineering andm etal-organic framework communities. [15] Recently,b all millinga nd other mechanochemicalt echniques have been explored as methods to complement the synthetic toolkit. [16] Running reactions under mechanochemical conditions not only offers am ore sustainable way to carry out solvent-minimized/free reactions but can also lead to decreased reactiont imes, increased selectivity,o rd ifferent reaction outcomes when compared to results obtained from solution-based reactions. [17] Herein we describe ag reen methodf or the Reformatsky reaction by using the ball mill mechanical activation of elemental zinc in air.
Increasing the amount of zinc to 2equivalents resulted in an 81 %y ield of the desired hydroxy ester product 3 (Table 1, entry 2). Further increasing the amount of zinc led to no significant increasei ny ield ( Table 1, entries 3a nd 4). Rather than increasing the equivalents of zinc, increasing the amount of ethyl 2bromoacetate (2)f rom 1.2 to 2.0equivalents also led to no real difference in the observed yield (Table 1, entries 5a nd 6). With the optimized ratio of reagents in hand, ar eaction time study assessed four individual reactiont imes of 0.5, 1, 1.5, and 2h (Table 1, entries 2a nd 7-9), which indicated that the reaction needs 2h to afford complete conversion.A control experiment, whereby zinc was omitted from the reaction, returned none of the desired product.
We then applied the optimized conditions to af urther 11 commercially availablef orms of zinc ( Figure S1). Although, the zinc forms had variousp article sizes, which may lead to differences in the ratio betweenz inc oxide layer and zinc metal, a fixed mass (2 mmol, 0.130 g) of each sample was employed. Pleasingly, we found that in all cases the mechanochemical Reformatsky reaction was successfuli rrespective of form of zinc that wasu sed (Table 2). Notably,t here appears to be ag eneral trend that the forms with ah ighers urface area/volumer atio performed better for the Reformatsky reactionu nder neat ballmilling conditions, this is perhaps contrary to prediction as these metal forms should also contain ah igher proportion of zinc oxide.
[ a] Yield determined by 1 HNMR spectroscopy with mesitylene as internal standard.
[b] Yield determined by GC with mesitylene as internal standard. ing conditions using identicalr eagents (Scheme 4B). The solution-based reactioni nd ry THF and under nitrogen atmosphere at 50 8Cw ith either zinc flakes or granular zinc (no additive used) resultedi nl ow yields of 7a nd 4%,r espectively (Scheme 4B), whereas under ball-millingc onditions without any solvent, inert gas, or additive (Table2), the reactionp roceeded smoothly in 2handa ll formso fz inc explored were effective for this transformation.
In conclusion, ar eliable, operationally simple one-jar onestep mechanochemicalR eformatsky reactionh as been developed. By utilizing the organozincg enerated in situ upon milling, this method avoids the requirement for dry solvents, inert gases, and chemical additives and thus furnishes ap rocess where the green metrics are improved.