Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Chlorides with Primary Alkyl Chlorides
Alkyl chlorides and aryl chlorides are among the most abundant and stable carbon electrophiles. Although their coupling with carbon nucleophiles is well developed, the cross-electrophile coupling of aryl chlorides with alkyl chlorides has remained a challenge. We report here the first general approach to this transformation. The key to productive, selective cross-coupling is the use of a small amount of iodide or bromide along with a recently reported ligand, pyridine-2,6-bis(N-cyanocarboxamidine) (PyBCamCN). The scope of the reaction is demonstrated with 35 examples (63%\xc2\xb116% ave yield) and we show that the Br\xe2\x88\x92 and I\xe2\x88\x92 additives act as co-catalysts, generating a low, steady-state concentration of more-reactive alkyl bromide/iodide.
<p>Cross-electrophile coupling has rapidly become an important approach to the synthesis of Csp2-Csp3 bonds,1 but engaging less reactive C-Cl bonds, outside of activated systems2 or intramolecular reactions,3 has proven challenging. Indeed, unactivated C-Cl bonds are well-tolerated functional groups4 in cross-electrophile coupling methods (Scheme 1).5,6 The ability to cross-couple with organic chlorides is valuable for several reasons – first, organic chlorides are more abundant than organic bromides or organic iodides;7 second, the low reactivity of the C-Cl bond allows it to be introduced early in a synthesis and later diversified.8,9,10</p><p>The central challenge presented by C-Cl bonds in cross-electrophile coupling is the need for higher reactivity without sacrificing selectivity (Scheme 1). While the homodimerization of alkyl chlorides11 and aryl chlorides8c has been reported, no general cross-selective approach has yet been found.12 Recently, Zhang reported couplings of a variety of aryl chlorides, but only with an excess of ClCF2R reagents.13 Several groups have reported on the coupling of aryl chlorides with alkyl bromides14 or tertiary alkyl oxalate esters.15 However, the coupling of chlorobenzene with a simple alkyl bromide provided less than 25% yield of cross-coupled product.14a Switching to an alkyl chloride further diminishes selectivity and yield using our standard conditions (Scheme 1).16</p><p>Based upon our proposed mechanism for the coupling of aryl iodides with alkyl iodides,17–18,19, overcoming this dual reactivity-selectivity challenge requires a catalyst that selectively reacts with the Ar-Cl over the Alkyl-Cl, yet can slowly generate an alkyl radical from the Alkyl-Cl starting material. Herein we show that this can be accomplished through the use of salt additives to maintain a very low, steady-state concentration of an alkyl bromide/iodide and a uniquely selective pyridine-2,6-bis(N-cyanocarboxamidine) (PyBCamCN)20,21 ligated nickel catalyst (Scheme 1).</p><p>During reaction development, we observed a strong synergistic effect between the catalyst and the presence of substoichiometric amounts (10–30 mol%) of bromide or iodide (Table 1 and Supporting Information Figures S1, S4-S7). While no catalysts were found that provided high yields of product in the absence of bromide or iodide, high selectivity could be achieved in reactions with PyBCamCN ligand and NiBr2(dme) or NiI2•4H2O; and in reactions with PyBCam ligand and NiBr2(dme) (Table 1, bold-faced entries). Reactions with bipyridine (bpy) or pyridine 2-carboxamidine (PyCam) ligands, which are optimal for the coupling of aryl bromides with alkyl bromides,20,22 favored formation of aryl dimer products (bpy) or hydrodehalogenated arene (PyCam) without consuming the alkyl chloride. Reactions with terpyridine (tpy), which is useful for the dimerization of alkyl halides,23 converted alkyl chloride to dimeric and hydrodehalogenated products without consuming aryl chloride. In contrast to tpy, reactions with 4,4′,4″-tri-tert-butyl-2,2′:6′,2″-terpyridine (tpy‴), which is useful in Negishi cross-coupling reactions of alkyl halides,24 consumed both substrates but formed approximately 1:1:1 product/alkyl dimer/aryl dimer.25 See also Chart S1 in the Supporting Information.</p><p>Routine optimization with PyBCam and PyBCamCN demonstrated that PyBCamCN was superior, that reactions were best conducted at 60–80 °C, and that a variety of iodide and bromide additives provide similar results.25 Reactions with bromide additive provided the highest yields when the alkyl chloride was added slowly, either portionwise via syringe or dropwise through an addition funnel. Reactions with iodide additive did not benefit from slow addition. The primary side products in both cases are the alkyl dimer and aryl hydrodehalogenated product.</p><p>The optimized conditions were then applied to a variety of primary alkyl chlorides and chloroarenes (Scheme 2). Electron-rich aryl chlorides, which were unreactive under our previously published conditions, coupled in 69–72% yield (3b, 3f, 3g, 3r). However, a more sterically hindered aryl chloride, 2-chlorotoluene, coupled poorly (3e, 15% yield). While we had coupled electron-poor aryl chlorides with alkyl bromides previously,14 under these conditions electron-poor aryl chlorides could be coupled with alkyl chlorides for the first time, with yields ranging from 53–73% yield (3c, 3h, 3i, 3s, 3u, 3v). As expected with PyBCam ligands,20 a variety of heterocycles could be coupled, including both electron-poor quinoline (3s, 63%) and pyridine (3u, 66% and 3v, 73%); and electron-rich indole (3r, 71%) and thiophene (3t, 33%). A particular advantage of cross-electrophile coupling is tolerance for alkyl halides with β-leaving groups (3z-3ad). The analogous organometallic reagents would be prone to elimination. Finally, secondary alkyl chlorides do couple under these conditions, but in lower yield (3ai, 44%).</p><p>Despite the higher temperatures, functional group compatibility remained broad. The low basicity of the conditions allowed us to tolerate both aryl and alkyl pinacol boronic acid esters (3o-3q, 49–73% yield), providing opportunities for further elaboration of the products. Acidic N-H (3ag, 60%) and O-H (3ae, 57%) groups are tolerated, which would be a challenge for organomagnesium or organozinc reagents.26 As a testament to the low basicity of the conditions, a free thiol was tolerated (3g, 70% yield), avoiding competing SN2 with the alkyl electrophile and S-arylation (pKa of thiophenol in DMSO is 10.3,27 which makes it more acidic than acetic acid).28 On the other hand, despite the presence of Lewis acids (ZnII salts, Li+ salts) at 60–80 °C, Boc groups on nitrogen were still tolerated (3ag, 60%; 3ah, 71%). While esters were tolerated, we did observe scrambling when two different esters were present due to transesterification (for example, methyl and ethyl ester exchange). For this reason, we coupled chloroarenes bearing esters (3i, 3j) with 1-chlorooctane. Other functional group highlights include a benzylic diethylphosphonate ester (3n, 51%) and a trimethoxysilane (3y, 32%). Despite the low yield, the cross-coupling to form trimethoxysilane product 3y is notable because it is a different approach29,30 to forming functionalized silanes that could be useful in attaching molecules to glass or silica.31 As in our previous studies on cross-electrophile coupling reactions with less reactive substrates, this chemistry can be scaled up using standard techniques (3ac).32</p><p>The distinctive feature of this reaction, when compared to other cross-electrophile couplings of aryl halides with alkyl halides, is the ability to engage two relatively unreactive substrates in a selective manner (Scheme 1). There are three keys to the success of this method.</p><p>First, LiCl was essential for efficient reduction of the nickel catalyst by the zinc surface. We have recently noted that ZnCl2 can have an inhibitory effect on reduction of nickel catalysts and that lithium chloride is among the best agents for overcoming inhibition,33 consistent with previous reports on reduction of organic molecules.34 Here too, reactions conducted without LiCl resulted in 3% formation of the cross-coupled product and primarily returned both substrates (Supporting Information Figure S2). We also verified that neither organic chloride reacts directly with zinc to form an organozinc reagent (Supporting Information Figure S2).</p><p>Second, halide exchange plays a key role by increasing the reactivity of the alkyl chloride. We found that 10–30% of bromide or iodide, regardless of how it was introduced, was essential for reasonable reaction rates (Scheme 3 and Supporting Information Figures S4-S7). Importantly, the low concentration of bromide was essential; reactions run without any bromide (Scheme 3d) or with only alkyl bromide (Scheme 3e) provided lower yields than reactions with a catalytic amount of bromide (Scheme 3a – Scheme 3c and Table 1).</p><p>Studies on halide exchange showed that it is fast compared to the rate of reaction (reaching equilibrium in 1–2 h vs 24 h for reaction time) and unfavorable (Supporting Information Figure S8-S16). Significantly, the presence of zinc and lithium salts altered the equilibrium to more strongly favor alkyl iodide/bromide. This led to the counterintuitive outcome that increasing total chloride concentration increased alkyl iodide concentration. Under concentrations of salts chosen to mimic those present catalytic reactions, we found that the amount of alkyl iodide increased as the concentration of ZnCl2 increased, although the ratio of alkyl-Cl/alkyl-I remained large in all cases (≥98:2, Figure S10 and S16). We tentatively attribute this phenomenon to the favorable formation of LiZnCl3 over LiZnCl2Br or LiZnCl2I, resulting in sequestration of chloride as the concentration of Zn2+ increases at later reaction times.35 The halogen exchange is also somewhat faster than reported for exchanges in amide solvents with only sodium bromide, but this process could be catalyzed by zinc: catalysis of alkyl halogen exchange by titanium, zirconium, rhodium, and iron salts has been reported.36</p><p>While iodide exchange to enhance the reactivity of alkyl bromides,14 sulfonic acid esters,37 epoxides,38 and chlorides11 in cross-coupling reactions is now well established, the use of bromide is more rare.39 In cases where iodide co-catalysis isn't practical, the use of bromide co-catalysis should be considered.</p><p>Finally, studies with a variety of ligands revealed that PyBCam nickel catalysts are unique in being able to react with both substrates at similar rates, even with activation by halide exchange (Table 1 and Supporting Information Figure S1). Compared to nickel complexes of tpy‴, which could also react with both substrates but formed both biaryl and bialkyl, nickel PyBCam catalysts avoid biaryl formation entirely and form only small amounts of alkyl dimer. The origin of these differences in reactivity are not yet clear and are the subject of ongoing studies, but it is clear that PyBCam and PyBCamCN are a distinctive, new class of tridentate ligands for nickel catalysis.40</p><p>In conclusion, the first selective cross-electrophile coupling reaction of aryl chlorides with primary alkyl chlorides has been developed by the synergistic effect of three changes: a new, selective ligand (PyBCamCN), LiCl to enhance catalyst turnover, and bromide/iodide co-catalysis. The mechanism by which PyBCamCN improves yields is under investigation and will be reported in due course. We expect that the generally unreactive nature of alkyl and aryl chlorides should make this new method to functionalize them a useful addition to synthesis.</p>