A Novel Electromagnetic Mill Promoted Mechanochemical Solid-State Suzuki–Miyaura Cross-Coupling Reactions: Ultra-Low Catalyst Loading without Molecular Dispersants

The Nobel-prize-winning Suzuki-Miyaura cross-coupling(SMC) is a practical and attractive strategy for the construction of C-C bonds in both academic and industrial settings. However, the development of solid-state SMC reactions remains extremely scarce. Herein, we report the rst electromagnetic mill(EMM) promoted solid-state SMC reaction using ultra-low palladium loading(0.05 mol%) without any molecular dispersants. This protocol exhibits substantially broadened substrate scope, good functional groups tolerance and ecient gram-scale synthesis, especially, provides relative high yields. The utility of this strategy was exemplied in the modication of photoluminescence molecules, cross-coupling of slightly soluble compound and synthesis of several important bioactive molecules. Furthermore, the XPS analyses on the oxidation state changes of palladium catalyst suggest the involvement of Pd I intermediate which might be the active catalytic species. This solvent-free solid-state EMM-SMC was potential developed into industrially attractive and environmentally friendly routes, and the EMM system developed in this study could unlock broad areas of chemical space for solvent-free solid-state metal-catalyzed syntheses of valuable targets in various scientic elds.

mechanochemistry to organic transformations is more recent  . So far, most of the examples are focusing on grinding or milling, and the process might promote the reactivity by ensuring thorough mixing and agitation of reactants, particle comminution down to nanometer sizes and creation of activated (amorphous) high-energy phases or zones of high temperature and pressure, which could not be reached in conventional stirring 42,43 .
The Nobel-prize-winning Suzuki-Miyaura cross-coupling(SMC) is a practical and attractive strategy for the construction of C-C bonds in both academic and industrial settings [44][45][46][47] . More than 60% of the C−C bond is constructed via SMC in medicinal chemistry 48 . Importantly, the classic asymmetric biaryl compounds constructed via SMC are an extensive structural scanfold in pharmaceuticals 45,[49][50][51][52] .
In addition, the scope of substrates is signi cantly restricted to electrondefcient aryl halides with low conversion rates. Furthermore, liquid-assisted grinding (LAG) by using a small amount of solvent, has emerged as a common strategy for solid-state reactions. Notably, Ito group demonstrated an ole n- transformations. However, it is still challenging to realize solvent free strategies for solid-state organic reactions avoiding any liquid additives due to the poor mixing e ciency and deleterious aggregation of reactants and/or catalysts. Thus we sought to design a new concept to solve this issue in solid-state SMC.
The electromagnetic mill(EMM) is a novel grinding device, using small ferromagnetic particles as the grinding media in a rotating electromagnetic eld 65 . The basic elements of the EMM are inductor of rotating magnetic eld and placed in its axis tube, serving as a working chamber. Unlike the conventional ball mills, the mill housing is stationary while the grinding takes place in the working chamber using some small ferromagnetic rods to move as grinding media. The movement of ferromagnetic rods is caused by the action of the vortex electromagnetic eld. The effectiveness and e ciency of the EMM process is dependent on the size parameters of the rods and the speed and intensity of the rotating electromagnetic eld. So far, the EMM is only utilized in shredding of the raw material and ultra-ne comminution. 68-71 Considering on the issue of low reaction e ciency due to aggregation in solid state, we design and develop a new EMM equipment for solid-state coupling reactions, which might potentially solve this problem. Herein, we report the rst EMM promoted solid-state SMC reaction using ultra-low catalyst loading without molecular dispersants ( Figure 1B-3).
Subsequently, we turned our attention to the scope of aryl bromides (Table 2b). Simple aryl bromides bearing electron-withdrawing groups such as cyano, aldehyde, nitro, carbonyl and chloro groups provided the desired products (4a-4e) in good to high yield (64%-92%). The strong electron-donating group substituted aryl bromides such as 2-bromo-4,6-dimethylaniline and 4-bromo-N,N-dimethylaniline proceeded smoothly to furnish the coupling products 4f and 4g in 75% and 72% respectively. The pterphenyl and 2-phenylnaphthalene derivates 4h and 4i were obtained e ciently under the standard conditions (82% and 93%). (4-Bromophenyl)(phenyl)methanone and 5-bromo-2,3-dihydro-1H-inden-1-one coupled with p-bromoacetophenone to afford 4j and 4k in high yields (84% and 85%). In addition, aryl bromides bearing thiophene, dibenzothiophene, 2-acetylpyridine or indole motif(Core of various intermediates for drugs and OLED), produced the correspinding products in moderate to high yields (4l-4p). Then the introduction of multi-aromatic scafford to boronic acid could also proceed e ciently to produce the corresponding compounds in 62%-81% yield (4q-4t). Furthermore, some aryl iodides were also investigated which delivered the corresponding products in good yields (5a-5c). Especially, the unprotected phenol could survive very well under the standard conditions (5a-5b).   To further investigate the functional group compatibility and practicality of the developed EMM-SMC, it was used to the modi cation of photoluminescence molecules. The scaffords of photoluminescence molecules bearing anthracene-9,10-dione, triphenylamine, dibenzopyrrole or perylene worked smoothly to generate the corresponding molecules in good to excellent yields(6a: 95%, 6b: 58% and 6c: 76%) ( Table  3). As shown at the bottom of table 3, the uorescence of the core scaffolds could be regulated e ciently via EMM-SMC reaction, such as introducing anisole group to anthracene-9,10-dione 1-6a could change the uorescence from light blue to yellow(6a), acetophenone regulated the uorescence of triphenylamine from blue to light green (6b) and the installation of anisole to perylene could induce strong yellowishgreen emission (6c)(in chloroform).
Subsequently, the EMM-SMC reaction was applied in the synthesis with solubility issues. Aryl halides with a solubility of 10 −2 −10 −3 M, designated "slightly soluble" in the U.S. Pharmacopoeia 72 often require a large amount of solvent in homogeneous solution based reactions, leading to the cross-coupling very slow and ine cient. To our delight, the transformation of the insoluble aryl halides could proceed e ciently under EMM conditions without neither molecular dispersant nor heating, delivering the corresponding products in good yields (7a: 74%, 7b:87%, 7c: 63%). On the other hand, the target molecules with poor solubility could also be furnished under the standard conditions, providing 7d in 66% and 7e in 85% yields. Table 5. Synthesis of Bioactive Molecules via EMM-SMC. a Furthermore, we examined the EMM-SMC reaction in the synthesis of bioactive molecules. The o-tolyl benzonitrile (OTBN) utilized in the synthesis of six different sartan-class drugs for the treatment of hypertension, could be e ciently achieved via EMM-SMC reaction of 2-bromobenzonitrile with ptolylboronic acid (8a: 72%) (Eq 1, Table 5). 73 A furan-containing pharmaceutical intermediates 8b (CYP17 inhibitor) were successfully prepared in 63% yield (Eq 2, Table 5). 74 The key intermediate 8c for GABA R2/3-agonist which was used for treating anxiety, was furnished e ciently under the standard conditions (8c: 80%) (Eq 3, Table 5). Di unisal is a non-steroidal drug with analgesic, anti-in ammatory and antipyretic properties similar to aspirin. The biaryl scafford 8d, core of di unisal, was e ciently prepared by using 5-bromo-2-chlorobenzonitrile and (2,4-di uorophenyl)boronic acid (8d: 87%) (Eq 4, Table 5).
The nicotinamide fungicide Boscalid which was developed by BASF, exhibit a broad spectrum of bactericidal activity and e cacy against various of fungal disease. [75][76][77] One of the industrial production routes is a two-step process using 2-iodophenylaniline, 4-chlorophenylboronic acid and 2-chloronicotinyl chloride. However, the high cost of 2-iodophenylaniline led to this route less competitive. Through the EMM-SMC reaction, inexpensive 2-bromoaniline, instead of 2-iodophenylaniline, could work e ciently to provide the boscalid in 71% yield for two steps Eq 5, Table 5).
With regard to this solid-state EMM-SMC reaction, the ultra-low palladium loading and highly e cient transformation of this strategy cause our interest to the reaction mechanism. Generally, the classic SMC reaction catalyzed by palladium/phosphine ligand is quite sensitive to oxygen, that's why inert gas protection is necessary; however, this procedure proceeded e ciently under air conditions with only 0.05 mol% palladium loading. Notably, Hartwig et al. reported a palladium(I) dimer catalyzed SMC which is airstable and could be nished in 15 min. 78 Recently, Schoenebeck group reported a series of work on palladium(I) dimer catalyzed cross-coupling reactions which exhibited excellent catalytic reactivity. [79][80][81][82][83][84][85] Inspired by the pioneer work and the performance of this system, we wonder if it is possible to generate a precatalyst palladium(I) dimer in situ under EMM conditions. So we utilized XPS analysis to characterize the changes of valence state of palladium during the reaction (Figure 2). In the blank sample, Pd(OAc) 2 (1.0 equiv.) was mixed with DavePhos (1.5 equiv.), and the XPS analysis of Pd 3d 5/2 shows the binding energy value of 336.93 eV, which is assigned to Pd(II) species (Figure 2a). When substrates 1a and 2a were subjected to the catalyst system for 10 min, a new curve shows that the binding energy value of Pd 3d 5/2 shifts from 336.93 eV (Pd 2+ ) to 336.06 eV which is assigned to Pd + 3d 5/2 (Figure 2b, curve in light green). Meanwhile, the binding energy value of Pd 0 3d 5/2 at 335.5 eV was also detected (Figure 2b, curve in pink). After the reaction was nished, the signal of binding energy value of Pd 0 3d 5/2 (335.5 eV) was enhanced obviously indicating the increasing of Pd 0 (Figure 2c, curve in pink). These results strongly indicated Pd II complex was reduced to Pd I during the transformation, however, we could not con rm if a palladium(I) dimer was involved or not. Although we performed a series of control experiments to capture some radical intermediates using free radical scavenger or isolate key intermediates, the highly reaction e ciency and ultra-low catalyst loading made it di cult to obtain more information, and the mechanism is still unclear.
Very recently, Galán-Mascarós 86 , Kiciński 87 , Chatenet/Carrey 88 and Ding 89 successively demonstrated that an external magnetic eld could signi cantly enhance the catalytic activity of catalysts in the oxygen reduction reaction (ORR) and oxygen-evolution reactions (OER). Galán-Mascarós found a trend with a negligible effect for non-magnetic catalysts but maximum enhancement for highly magnetic ones in the magnetic nature of the catalysts. In this catalysis, the catalytic activity of possibly involved magnetic palladium(I) complex might be enhanced under the magnetic eld via promoting the electron transfer. To investigate the effect of magnetic eld to the SMC reaction, three control experiments were performed in toluene at different temperature without magnetic eld (Table 6). Under the EMM conditions for 1 hour, 3a was isolated in 99% yield (Entry 1), however, the yields decreased sharply when the reaction were conducted in toluene. Only 27% yield of 3a was obtained with 66% 1a recovered at room temperature (Entry 2). When the reaction was heated to even 80 o C, the coupling reaction could not be nished with 21% of 1a recovered (Entries 2-4). Notably, the reactions performed in toluene generated homocoupling products 3a-2 in 7%, 10%, 12% respectively. However, the homocoupling was totally suppressed under the EMM conditions. All of these results indicated that the EMM conditions could enhance the catalytic activity signi cantly. In summary, we have developed the rst EMM promoted solid-state SMC reaction using a catalytic system consisting of Pd(dppf)Cl 2 /DavePhos. While few previous ball-milling palladium-catalyzed solidstate coupling reactions have been reported, the substrate scope limitation, low conversion rates, using of molecular dispersants and high palladium loading signi cantly limit their application. Under this EMM system, the solid-state SMC could be successfully achieved using ultra-low catalyst loading(0.05 mol%) without any molecular dispersants. This strategy shows broad substrate scope, good functional groups tolerance and e cient gram-scale synthesis. Furthermore, its utility was exempli ed in the modi cation of photoluminescence molecules, cross-coupling of slightly soluble compound and synthesis of several important bioactive molecules. Then, the XPS analyses on the oxidation state changes of palladium catalyst suggest the involvement of Pd I intermediate which might be the active catalytic species. Compared with the EMM-SMC, solution-based conditions afforded relative lower yields within same reaction time; even so, homocoupling byproduct was also detected. Although the results indicate EMM system exhibit excellent catalytic e ciency, the effect of magnetic eld is still unclear. Finally, we anticipate that this solvent-free solid-state EMM-SMC could be developed into industrially attractive and environmentally friendly routes, and the EMM system developed in this study could unlock broad areas of chemical space for solvent-free solid-state metal-catalyzed syntheses of valuable targets in various scienti c elds.

Data availability
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