Iron‐Catalyzed Cross‐Coupling of Alkynyl and Styrenyl Chlorides with Alkyl Grignard Reagents in Batch and Flow

Abstract Transition‐metal‐catalyzed cross‐coupling chemistry can be regarded as one of the most powerful protocols to construct carbon–carbon bonds. While the field is still dominated by palladium catalysis, there is an increasing interest to develop protocols that utilize cheaper and more sustainable metal sources. Herein, we report a selective, practical, and fast iron‐based cross‐coupling reaction that enables the formation of Csp−Csp3 and Csp2−Csp3 bonds. In a telescoped flow process, the reaction can be combined with the Grignard reagent synthesis. Moreover, flow allows the use of a supporting ligand to be avoided without eroding the reaction selectivity.

describe herein our efforts to develop ar obustp rotocol to cross-couple both styrenyl and alkynyl chlorides with alkyl Grignardr eagents by using an Fe catalysta nd an NHC ligand. [15] This method provides as et of conditions that are both practical and widely applicable in CspÀCsp 3 and Csp 2 À Csp 3 bond-formingr eactions. Interestingly,t he Fe-based coupling reaction could be translated to flow and was combined with an inline generation of Grignard reagents. Furthermore, the flow strategy allowed the reaction to be carried out under mild conditions whilst avoiding the use of an NHC ligand, thus simplifying the overall process.
Expanding the substrate scope to involve styrenyl chlorides in this Fe-catalyzed cross-coupling protocol permitted us to forge Csp 2 ÀCsp 3 bonds as well ( Figure 2). Interestingly,f or most substrates, the reactionc ould be completed at room temperature without adding any supporting ligand. b-Chlorostyrene can be rapidly and efficiently coupledw ith assorted aliphatic (4a-g,9 0-96 %y ield) and aromatic (4h)( 97 %y ield) Grignardn ucleophiles. The protocol is easily scalable without reduced efficiency (4f,8mmol, 90 %y ield). b-Chlorostyrenes bearing electron-neutral( 4i-l), -donating (4m-q), and -withdrawing groups (4r)a tt he ortho-, meta-a nd para-positions are readily tolerated (89-97 %y ield). The reaction does not display ag reat sensitivity to steric hindrance, as both naphthyl substrates (4s,t,9 1-94 %y ields) and a-substituted b-chlorostyrenes (4u,v,9 4% yield) weree fficiently coupled with cyclo- hexylmagnesium chloride. Double functionalization was also possible, albeit at as lightly diminished yield (4w,5 7% yield). The reaction was stereoselective in all cases and even the cross-coupled product derived from (Z)-b-chlorostyrene was obtained in good yield and with retained stereoselectivity( 4x, 93 %y ield). Next, we investigated the possibility to telescope both the Grignardr eagent synthesis and the iron-catalyzed cross-coupling transformation in as ingle, streamlined continuous-flow process. The combinationo ft hese two individual steps allows the safe control of the exotherm of the Grignard reagent syn-thesis, [16] to keep the total inventory of potentially hazardous Grignardr eagents low andt ou se cheap organohalides as startingm aterials. [17] For the preparation of the Grignard reagent, we filled an open columnw ith magnesium according to the procedurer eported by Alcazar et al. [18] Over this magnesium packed-bed reactor,asolutiono fa lkyl or aryl halide was directeda nd the generated Grignard reagent was merged with the reagents required for the Fe-catalyzed cross-coupling transformation ( Table 2). [19] The combined reactionm ixture was fed to ac apillary microreactor (perfluoroalkoxy alkane, PFA; Figure 2. Scope of the iron-catalyzed cross-coupling between styrenylchlorides and alkyl Grignard reagents. Reactionconditions: 0.5 mmol 3, 0.6 mmol R'MgCl, 1mol %[ Fe(acac) 3 ]. in 2.5 mL THF at roomtemperature.
[b] Scale-up experiment on an 8mmol scale.
[d] The Z/E ratio of starting material 3x was 91:9 and of product 4x was 88:12. Table 2. Te lescoped organomagnesiumb romide synthesis and iron-catalyzed cross-coupling in flow.F or detailed reaction conditions, see the SupportingInformation.
In conclusion, we have developed ap ractical and mild ironcatalyzed cross-coupling method to establish Csp-Csp 3 and Csp 2 -Csp 3 linkages. The protocol utilizes an NHC ligand to efficiently couplea lkynylc hlorides and alkyl Grignard reagents, while no supporting ligand is neededf or the functionalization of styrenyl chlorides. Interestingly,t he Fe-based cross-coupling reactionc an be translated to flow and be combinedw ith the synthesis of Grignard reagents in as ingle, uninterrupted continuousp rocess. As alient feature of the flow protocol is that the use of an NHC ligand can be avoidedf or the Csp-Csp 3 coupling without compromising the reaction selectivity,w hich is attributed to the improved temperature control in am icroreactor.