catalysts Article
Novel Magnetically-Recyclable, Nitrogen-Doped Fe3O4@Pd NPs for Suzuki–Miyaura Coupling and Their Application in the Synthesis of Crizotinib Kai Zheng 1 , Chao Shen 1,2, * , Jun Qiao 2, *, Jianying Tong 2 , Jianzhong Jin 2 and Pengfei Zhang 3 1 2 3
*
School of Chemistry and Environmental Engineering, Jiangsu University of Technology, Changzhou 213001, China;
[email protected] College of Biology and Environmental Engineering, Zhejiang Shuren University, Hangzhou 310015, China;
[email protected] (J.T.);
[email protected] (J.J.) College of Material Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, China;
[email protected] Correspondence:
[email protected] (C.S.);
[email protected] (J.Q.); Tel.: +86-0571-88297172 (C.S.); +86-0571-88297103 (J.Q.)
Received: 5 September 2018; Accepted: 22 September 2018; Published: 10 October 2018
Abstract: Novel magnetically recyclable Fe3 O4 @Pd nanoparticles (NPs) were favorably synthesized by fixing palladium on the surface of nitrogen-doped magnetic nanocomposites. These catalysts were fully characterized by Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), transmission electron microscopy (TEM), thermogravimetric analysis (TG), and X-ray photoelectron spectroscopy (XPS). The prepared catalyst exhibited good catalytic activity for Suzuki–Miyaura coupling reactions of aryl or heteroaryl halides (I, Br, Cl) with arylboronic acids. These as-prepared catalysts could be readily isolated from the reaction liquid by an external magnet and reused at least ten times with excellent yields achieved. In addition, using this protocol, the marketed drug crizotinib (anti-tumor) could be easily synthesized. Keywords: heterogeneous catalyst; magnetically; palladium catalysts; nitrogen-doped; Suzuki coupling; crizotinib
1. Introduction Catalysts are gaining increasing importance, due to their effective manner of solving energy and resource problems, which have become an important part of achieving sustainable development strategies in the 21st century [1,2]. Among the noble metals, palladium and nickel are the most useful catalysts for the formation of C–C bonds in organic transformations [3–5]. In the past, homogeneous Pd catalysts made significant progress in Suzuki–Miyaura coupling reactions; however, it is difficult to separate the products and reuse them. To overcome the drawbacks of homogeneous catalysts, heterogeneous catalysts were significantly explored [6–10]. Heterogeneous catalysis has some advantages such as a recyclable catalytic systems, nontoxic ligands, and a lower amount of palladium residues in products [11–14]. The recovery of Pd catalysts from reaction systems is not easy, and attempts to solve the problem were made by immobilizing the active metal species on supports, such as carbon, silica, metal oxide, polymer, and nanocomposites [15–20]. The magnetic core/shell-supported catalyst is an excellent solution, and its intrinsic magnetic properties enable the efficient separation of the catalysts from the reaction system with an external magnetic field [21,22]. For example, Kumar et al. reported the use of Fe3 O4 @C/Pd as an excellent catalyst for the hydrogenation of aromatic nitro compounds, Suzuki coupling, and sequential reactions; the reactions worked well and gave excellent yields [23]. Sun and coworkers found that the magnetic Fe3 O4 @C/Pd Catalysts 2018, 8, 443; doi:10.3390/catal8100443
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catalyst showed high catalytic for the activity yield of biphenyl, andof it could maintain activity even Fe 3O4@C/Pd catalyst showed activity high catalytic for the yield biphenyl, and it90% could maintain after being recycled ten times [24]. Fang etten al. demonstrated that magnetic Fe3 O4 @C/Pd microsphere 90% activity even after being recycled times [24]. Fang et al. demonstrated that magnetic catalysts were active in Suzuki coupling [25]. in Suzuki coupling [25]. Fe 3O4@C/Pd microsphere catalysts were active Nitrogen-doped carbon attracted much attention due todue its special good properties, Nitrogen‐doped carbonhas has attracted much attention to itsstructure, special structure, good and potential applications [26–30]. Zhang et al. reported that Pd@C–N’s high catalytic performance properties, and potential applications [26–30]. Zhang et al. reported that Pd@C–N’s high catalytic is attributed toisthe unique structure of the catalytic andsupport–metal support–substrate performance attributed to the unique structuresupport–metal of the catalytic and junctions. support– Wang’s foundWang’s that an group as-synthesized Pd/N–carbon nanotube (CNT) catalyst showed(CNT) high substrategroup junctions. found that an as‐synthesized Pd/N–carbon nanotube catalyticshowed activityhigh in the Heck reaction, the catalystand could reused at could least five times in catalyst catalytic activity inand thethat Heck reaction, thatbe the catalyst be reused at the aerobic oxidation of benzyl [31,32]. Movahed and [31,32]. coworkers demonstrated that the least five times in the aerobic alcohol oxidation of benzyl alcohol Movahed and coworkers good reactivitythat of the NP–high nitrogen-doped graphene (HNG) catalyst in Suzuki coupling was demonstrated thePd good reactivity of the Pd NP–high nitrogen‐doped graphene (HNG) catalyst attributed to the high degree of nitrogen in graphene sheets [33]. in graphene sheets [33]. in Suzuki coupling was attributed to the loading high degree of nitrogen loading Continuing our in in developing novel carbohydrate-derived catalysts for C–C Continuing ourlongstanding longstandinginterest interest developing novel carbohydrate‐derived catalysts for or C–S coupling reactions [34–38], we were interested in developing a green and efficient chemistry C–C or C–S coupling reactions [34–38], we were interested in developing a green and efficient protocol forprotocol C–C coupling reactions and related practical Herein, we describe Herein, the efficient chemistry for C–C coupling reactions and applications. related practical applications. we synthesisthe of aefficient magnetically-recyclable, nitrogen-doped Fe3 O4 @Pd catalyst for the Suzuki of describe synthesis of a magnetically‐recyclable, nitrogen‐doped Fe3O 4@Pd coupling catalyst for arylSuzuki or heteroaryl halides (I, or Br,heteroaryl Cl) with arylboronic acids. as-preparedacids. catalysts could be easily the coupling of aryl halides (I, Br, Cl) These with arylboronic These as‐prepared isolated from mixture using external magnet, and could be reused least ten catalysts couldthe be reaction easily isolated from the an reaction mixture using anthey external magnet, and at they could times withatexcellent In addition, the marketed drug crizotinib (anti-tumor) could be be reused least tenyields timesachieved. with excellent yields achieved. In addition, the marketed drug crizotinib (anti‐tumor) could using be easily easily synthesized thissynthesized protocol. using this protocol. 2. Results Results and and Discussion Discussion 2. The preparation O44@C/Pd @C/Pdand andFeFe involve three steps, shown 3O 4 @NC/Pd The preparation procedures procedures of of Fe Fe3O 3O 4@NC/Pd involve three steps, as as shown in in Scheme 1. Initially, prepared via a robust solvothermal reaction based 3 O4 particles Scheme 1. Initially, the the Fe3OFe 4 particles werewere prepared via a robust solvothermal reaction based on the on the high-temperature reduction FeCl 6Hethylene [39]. Then, thin carbon 2 O in ethylene high‐temperature reduction of FeClof 3·6H 2O3 ·in glycol glycol [39]. Then, a thina carbon layerlayer was was modified ethylenediamine by stirring a mixture of4,Fe andinEDA in 3 O4 , glucose, modified with with ethylenediamine (EDA)(EDA) by stirring a mixture of Fe3O glucose, and EDA water. water. The mixture was coated the surface the magnetite Fe3 O4 particles via carbonization The mixture was coated on the on surface of the of magnetite Fe3O4 particles via carbonization under under hydrothermal conditions Ultimately, andFe Fe3O catalysts were were 34O 4 @NC/Pd 3O 4 @C/Pdcatalysts hydrothermal conditions [40].[40]. Ultimately, thetheFeFe 3O @NC/Pd and 4@C/Pd obtained upon PdCl or Fe3or O4Fe @C3Oin4@C ethanol, followedfollowed by ascorbic-acid reduction, 2 to2Fe 4 @NC obtained uponadding adding PdCl to3 OFe 3O4@NC in ethanol, by ascorbic‐acid to generate Pd(0) nanoparticles. reduction, to generate Pd(0) nanoparticles. Glucose
PdCl2 Ascorbic acid
Hydrothermal
Fe3O4@C/Pd
Fe3O4@C
= Pd nanoparticles Fe3O4
H2N NH2 Glucose
PdCl2 Ascorbic acid
Hydrothermal Fe3O4@NC
Fe3O4@NC/Pd
Scheme O44@NC/Pd @NC/Pdcatalysts. catalysts. Scheme1.1.Synthesis SynthesisofofFeFe 3O 4@C/Pd and Fe3 3O 3O 4 @C/Pd
These as‐prepared as-prepared catalysts were characterized by infrared infrared analysis analysis (FT‐IR), (FT-IR), thermogravimetric These catalysts were characterized by thermogravimetric analysis (TG), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), analysis (TG), transmission electron microscopy (TEM), X‐ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD) and inductively coupled plasma-optical emission spectrometry (ICP-OES). X‐ray diffraction (XRD) and inductively coupled plasma‐optical emission spectrometry (ICP‐OES). 1 could correspond to the absorption band In Figure Figure 1, 1, the the presence presence of of absorption absorptionbands bandsatat673 673cm cm−1−could In correspond to the absorption band of − 1 −1 and 3386 cm −1 −1 −1 and of Fe–O and 1336 cm could correspond to the O–H bending vibrations; 1558 Fe–O and 1336 cm could correspond to the O–H bending vibrations; 1558 cmcm 3386 cm−1 are are associated C=O O–Hvibrations, vibrations,which whichconfirms confirmsthe the successful successful attachment attachment of of associated withwith the the C=O andand O–H nitrogen-doped carbon carbon on This also also reflects reflects the the carbonization of aminated nitrogen‐doped on the the surface surface of of Fe Fe33O O44.. This carbonization of aminated glucose during during the the hydrothermal hydrothermal process process and and suggests suggests the the presence presence of of large large amounts amounts of of hydrophilic hydrophilic glucose groups on The FTIR (c) and and Fe Fe33O O44@NC @NC(b) (b) were were similar similar groups on the the Fe Fe33O O44@NC @NC [41]. [41]. The FTIR spectra spectra of ofFe Fe33O O44@NC/Pd @NC/Pd (c) to Fe O (a), however the FTIR spectra of Fe O @C/Pd and Fe O @NC/Pd were different (Figure S1). 3 4 3 4 3 4 to Fe O4 (a), however the FTIR spectra of Fe3O4@C/Pd and Fe3O4@NC/Pd were different (Figure S1).
The existence of absorption bands at 1382 cm−1 (C–H) and 1250 cm−1 (C–O) confirmed the arylide was adsorbed by Fe3O4@NC/Pd catalyst after the catalytic reaction (Figure S2).
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The existence of absorption bands at 1382 cm−1 (C–H) and 1250 cm−1 (C–O) confirmed the arylide Catalysts xxFOR REVIEW 33of Catalysts2018, 2018, FOR REVIEWcatalyst after the catalytic reaction (Figure S2). of12 12 was adsorbed by8,8,Fe @NC/Pd 3 OPEER 4PEER Catalysts 2018, 8, x FOR PEER REVIEW
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Figure 1. Fourier-transform infrared (FTIR) spectra ofof (a) Fe (b) Fe O44@NC, @NC, and O4 @NC/Pd. Figure 1. infrared (FTIR) spectra (a) Fe and (c) Fe 33O 4@NC, Figure 1.Fourier‐transform Fourier‐transform infrared (FTIR) spectra of (a) Fe 3O O444,,,(b) (b)Fe Fe333O O and (c)(c) Fe3Fe 3O O434@NC/Pd. @NC/Pd. Figure 1. Fourier‐transform infrared (FTIR) spectra of (a) Fe3O4, (b) Fe3O4@NC, and (c) Fe3O4@NC/Pd.
The thermal stability of Fe O (a), FeFe and Fe33O O (c) proved by TG 3O 4 4@NC 3O 4 @NC/Pd The stability of 44 (a), 33O (b) 44@NC/Pd (c) then proved by The thermal thermal stability of3Fe Fe433O O (a), Fe O 4@NC @NC (b) (b) and and Fe Fe @NC/Pd (c) was waswas thenthen proved by TG TG ◦ The thermal stability of Fe 3 O 4 (a), Fe 3 O 4 @NC (b) and Fe 3 O 4 @NC/Pd (c) was then proved by TG analysis. Figure 2 shows that catalysts were to 250 andsuggests suggests that their high thermal analysis. Figure 22 shows that catalysts were stable that their high thermal analysis. Figure shows that catalysts werestable stableup up to to 250 250 °C °CCand and suggests that their high thermal analysis. Figure 2them shows that catalystswith were stable up to 250 °C and suggests that their high thermal stability allows them to compatible with most organic reactions. stability allows them to be compatible reactions. stability allows to be be compatible withmost mostorganic organic reactions. stability allows them to be compatible with most organic reactions. 100 100 100
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FigureFigure 2. Thermogravimetric analysis graphs ofof (a) (b)Fe Fe33O Fe O4 @NC/Pd. 2. analysis graphs (a) Fe 44@NC; (c) Fe Figure 2.Thermogravimetric Thermogravimetric analysis graphs of (a)Fe Fe 3O O444;;;(b) Fe @NC; (c)(c) Fe33O O44@NC/Pd. 33O 3OO 4 @NC; 3@NC/Pd. Figure 2. Thermogravimetric analysis graphs of (a) Fe3O4; (b) Fe3O4@NC; (c) Fe3O4@NC/Pd.
The TEM image of Fe O343O @NC/Pd is shown inFigure Figure These microspheres essentially The image of 44@NC/Pd 3. These microspheres essentially have The TEM TEM image of3Fe Fe O @NC/Pd is is shown shown in in Figure 3. 3. These microspheres essentially have aahave Thecore/shell TEM image of Fe3O4@NC/Pd shown diameter in Figureof 3.of These microspheres essentially have a final typical nanostructure and the the catalyst was about 300 nm. The final a typical core/shell nanostructure and average diameter the catalyst was about The typical core/shell nanostructure andthe theisaverage average diameter of the catalyst was about 300300 nm.nm. The final typical core/shell nanostructure and the average diameter of the catalyst was about 300 nm. The final morphology of Fe 3 O 4 @NC and Fe 3 O 4 @C shows a core–shell feature with Pd uniformly deposited on morphology Fe43@NC O4@NC andFe Fe33O O44@C feature withwith Pd uniformly deposited on morphology of Feof3 O and @Cshows showsa acore–shell core–shell feature Pd uniformly deposited morphology of FeTEM 3O4@NC and Fe3O4@C shows a core–shell feature with Pd uniformly deposited on the surface. The studies confirmed Pd NPs on the surface of the surface.The The TEMstudies studies confirmed confirmed the the incorporated PdPd NPs onon thethe surface of Fe Fe33O O44@NC @NC on the surface. TEM theincorporated incorporated NPs surface of Fe O 3 4 @NC the surface. The TEM studies confirmed the incorporated Pd NPsnanostructure. on the surface of Fe3O4@NC nanospheres and also indicated that the catalyst had a core–shell In addition, the nanospheres and also indicated that the catalyst had a core–shell nanostructure. In addition, the nanospheres and also indicated that that the catalyst hadhad a core–shell nanostructure. In In addition, thethe results nanospheres and also indicated the catalyst a core–shell nanostructure. addition, results mean the carbonization did not damage the core–shell structure. results mean the carbonization did not damage the core–shell structure. meanresults the carbonization did not damage the core–shell structure. mean the carbonization did not damage the core–shell structure.
Figure Figure3. 3.TEM TEMimages imagesof ofFe Fe33O O44@NC/Pd @NC/Pdcatalyst. catalyst. Figure TEMimages imagesof ofFe Fe33O catalyst. Figure 3. 3. TEM O44@NC/Pd @NC/Pd catalyst.
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As shown in Figure 4, the electronic properties of the Fe3O4@NC/Pd catalyst were probed by As shownAs in shown Figure in 4, Figure the electronic properties of the Fe3toOC1s, 4 @NC/Pd XPS analysis. 4a, the peaks corresponding N 1s, Ocatalyst 1s, andwere Pd 3s,probed 3p and by XPS analysis. As shown in Figure 4a, the peaks corresponding to C1s, N 1s, O 1s, andnitrogen Pd 3s, 3d were clearly observed in the XPS survey spectroscopy. This indicates that the 3p and 3d were clearly theThe XPSC1s survey This indicates that the nitrogen successfully doped the observed Fe3O4@Pd in NPs. peakspectroscopy. of Fe3O4@NC/Pd catalyst is shown in Figure 4b. successfully doped the Fe O @Pd NPs. The C1s peak of Fe O @NC/Pd catalyst is shown in Figure 4b. 3 4was associated with the C–C,3 implying 4 The main peak at 281.1 eV that most of the carbon atoms in The at 281.1 eV was the C–C, implying thatlattice. most of carbon themain Fe3O4peak @NC/Pd catalyst wereassociated arranged with in a conjugated honeycomb Asthe shown in atoms Figure in 4c, the were arranged inwere a conjugated lattice. As shownThe in Figure 4c, 3 O4 @NC/Pd theFebinding energycatalyst of Pd 3d 3/2 and Pd 3d5/2 331.1 eVhoneycomb and 336.2 eV, respectively. two peaks the binding energy of Pdpeaks 3d3/2 of and Pd 3d 336.2 eV, respectively. The tworeduced peaks 5/2 were 331.1 were the characteristic Pd(0), suggesting that eV the and absorbed Pd(II) was successfully were the characteristic Pd(0), suggesting that the was successfully reduced to Pd(0) nanoparticlespeaks underofascorbic‐acid reduction. Byabsorbed ICP‐OESPd(II) detection, the content of the Pd toelement Pd(0) nanoparticles under ascorbic-acid reduction. By ICP-OES detection, the content of the Pd loaded on Fe3O4@NC/Pd catalyst was found to be 5 wt%. element loaded on Fe3 O4 @NC/Pd catalyst was found to be 5 wt%. 4500
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(c) Figure XPS spectra 4@NC/Pdcatalyst, catalyst,(b) (b)CC1s 1sand and(c) (c)Pd Pd3d. 3d. Figure 4. 4. XPS spectra ofof (a)(a) FeFe 3 O3O 4 @NC/Pd
To thethe catalytic performance of these catalysts, Suzuki coupling were carried out as model Toevaluate evaluate catalytic performance of these catalysts, Suzuki coupling were carried out as reactions. The reactions were carried out using water as the solvent and by coupling 4-iodoanisole (1a) model reactions. The reactions were carried out using water as the solvent and by coupling with phenylboronic acid (2a), and using different reaction parameters such as theparameters base, the temperature, 4‐iodoanisole (1a) with phenylboronic acid (2a), and using different reaction such as the the time, thetemperature, dosage and the of the catalyst to obtain conditions. As shown in Table 1, base, the thekind time, dosage and the best kindreaction of catalyst to obtain the best reaction the Fe3 O4 andAs theshown magnetic not able to catalyze the reaction (Table 1, entries 1–3). conditions. in core–carbon Table 1, theshell Fe3Owere 4 and the magnetic core–carbon shell were not able to Fe and Fe3 O showed high reactivity, demonstrating, catalyze the reaction (Table 1, entries 1–3).good Fe3O4results @C/Pd due and to Fe3their O4@NC/Pd showed good results due 3 O4 @C/Pd 4 @NC/Pd to their high reactivity, demonstrating, respectively, that N‐doped carbon has a great influence on
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the catalytic results, and an increase in the nitrogen loading in carbon sheet leads to an increase in respectively, that N-doped carbon has a great influence on the catalytic results, and an increase in the the product yield (Table 1, entries 4, 5). Then, various bases such as K2CO3, NaOH, Na2CO3, KOH, nitrogen loading in carbon sheet leads to an increase in the product yield (Table 1, entries 4, 5). Then, Et3N and Cs2CO3 were also screened for their effect on the reaction (Table 1, entries 5–10); the best various bases such as K2 CO3 , NaOH, Na2 CO3 , KOH, Et3 N and Cs2 CO3 were also screened for their yield was obtained when KOH was used (Table 1, entry 8). Besides, the effect of different effect on the reaction (Table 1, entries 5–10); the best yield was obtained when KOH was used (Table 1, temperatures was explored and the results showed that 90 °C was more appropriate for the Suzuki entry 8). Besides, the effect of different temperatures was explored and the results showed that 90 ◦ C coupling than other temperatures and provided the highest yield of 96% (Table 1, entries 8, 11–14). was more appropriate for the Suzuki coupling than other temperatures and provided the highest yield Next, the effect of the catalyst dosage was examined and the best result was obtained when 10 mg Pd of 96% (Table 1, entries 8, 11–14). Next, the effect of the catalyst dosage was examined and the best was used as the catalyst (Table 1, entries 8, 16–18). Finally, it was found that the reaction after 0.5 h result was obtained when 10 mg Pd was used as the catalyst (Table 1, entries 8, 16–18). Finally, it was resulted in a higher yield (Table 1, entries 8, 19–20). found that the reaction after 0.5 h resulted in a higher yield (Table 1, entries 8, 19–20). Table 1. Optimization of reaction conditions. a. Table 1. Optimization of reaction conditions. a.
b (%) b (%) Entry Catalyst (mg)(mg) Base Base Temp C) Time Yield Entry Catalyst Temp(◦(°C) Time (h)(h) Yield 11 Fe4 3O4 90 1 1 ‐ Fe3 O K2 COK3 2CO3 90 Fe3 O K2 COK3 2CO3 90 22 Fe4 @C 3O4@C 90 1 1 ‐ 3 Fe O @NC K CO 90 1 3 4 2 3 3 Fe3O4@NC K2CO3 90 1 ‐ 4 Fe3 O4 @C/Pd K2 CO3 90 1 84 45 Fe3O4@C/Pd K2CO3 90 1 1 84 93 Fe3 O4 @NC/Pd K2 CO3 90 56 Fe4 @NC/Pd 3O4@NC/Pd K2CO3 90 1 1 93 94 Fe3 O NaOH 90 Fe3 O Na2 CO 90 67 Fe4 @NC/Pd 3O4@NC/Pd NaOH 90 1 1 94 92 3 Fe3 O KOH 90 78 Fe4 @NC/Pd 3O4@NC/Pd Na2CO3 90 1 1 92 96 9 Fe3 O4 @NC/Pd Et3 N 90 1 71 8 Fe3O4@NC/Pd KOH 90 1 96 10 Fe3 O4 @NC/Pd Cs2 CO3 90 1 83 911 Fe4 @NC/Pd 3O4@NC/Pd 90 1 1 71 66 Fe3 O KOHEt3N rt 10 Fe4 @NC/Pd 3O4@NC/Pd Cs2CO3 90 1 1 83 75 12 Fe3 O KOH 50 13 Fe3 O KOHKOH 70rt 11 Fe4 @NC/Pd 3O4@NC/Pd 1 1 66 90 14 Fe O @NC/Pd KOH 100 1 3 4 12 Fe3O4@NC/Pd KOH 50 1 75 95 15 Fe3 O4 @NC/Pd K2 CO3 50 1 70 13 Fe3O 70 1 1 90 16 - 4@NC/Pd KOHKOH 90 14 Fe4 @NC/Pd 3O4@NC/Pd 100 1 1 9595 c 17 Fe3 O KOHKOH 90 18 Fe3 O KOHK2CO3 90 15 Fe4 @NC/Pd 3O4@NC/Pd 50 1 1 7077 d 19 Fe3 O4 @NC/Pd KOHKOH 90 16 ‐ 90 1 0.5 ‐ 96 20 Fe3 O4 @NC/Pd KOH 90 0.2 90 17 Fe3O4@NC/Pd KOH 90 1 95 c d a The reaction 18 Fe3O4-iodoanisole 4@NC/Pd 1a (1 mmol), KOH 90acid 2a (1.5 mmol), 1 10 mg catalysts, 77 and conditions: phenylboronic base c 20 mg catalysts. d 5 mg catalysts. (1.5 mmol) air. b Isolated yield. 19 in 3 mL water Fe3Ounder 4@NC/Pd KOH 90 0.5 96 20 Fe3O4@NC/Pd KOH 90 0.2 90 a The reaction After obtaining the optimal reaction 1a conditions, substrate scope themmol), aryl halides conditions: 4‐iodoanisole (1 mmol), the phenylboronic acid 2aof(1.5 10 mg and b c d catalysts,acids and base mmol) As in 3shown mL water under 2, air.theIsolated yield. 20 mg catalysts. mg first arylboronic was (1.5 studied. in Table effect of different aryl iodides 5was catalysts. carried out using phenylboronic acid (2a) as a substrate. The result showed that the substrates with electron-releasing groups gave good yields when compared to electron-withdrawing groups in aryl After obtaining the 1–13) optimal conditions,orthe substrate scopesubstrates of the aryl halideslower and halides (Table 2, entries andreaction meta-substituted ortho-substituted showed arylboronic acids was studied. As shown in Table2, 2, the effect of different aryl iodides was first yields than the para-substituted arylhalides (Table entries 2,4–7,10–13). These results showed that carried out using phenylboronic acid (2a) as a substrate. The result showed that the substrates with the steric hindrance and electronic effect of substrates 1a–m had little effect on the Suzuki coupling electron‐releasing groups gave good yields when electron‐withdrawing groups in aryl under the optimized reaction conditions. Then, the compared efficiency oftothe protocol for the Suzuki coupling of halides (Table or 2, chlorides entries 1–13) meta‐substituted ortho‐substituted substrates showed lower aryl bromides withand corresponding boronicoracids was examined. The reaction conditions yieldsquite than effective the para‐substituted arylhalides 2, entries These results that were for the coupling of aryl(Table bromides with 2,4–7,10–13). boronic acids, resulting inshowed high yields the steric hindrance and electronic effect of substrates 1a–m had little effect on the Suzuki coupling (Table 2, entries 14–16). However, only a moderate yield were obtained when aryl chlorides were underasthe reaction conditions. Then, efficiency of the using protocol for the Suzuki coupling used theoptimized substrate (Table 2, entries 17–20). Thethe coupling reactions arylboronic acids were also of aryl bromides or chlorides with corresponding boronic acids was examined. The investigated, and the coupling products were obtained in good yields, the electron-releasingreaction groups conditions were quite for thecompared couplingto ofsubstrates aryl bromides with boronic acids, resulting in in arylboronic acid gaveeffective higher yields bearing electron-withdrawing groups high yields (Table 2, entries 14–16). However, only a moderate yield were obtained when aryl (Table 2, entries 21–26). Moreover, the optimized reaction conditions were effective for the Suzuki chlorides were used as the substrate (Table 2, entries 17–20). The coupling reactions using arylboronic acids were also investigated, and the coupling products were obtained in good yields,
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the electron‐releasing groups in arylboronic acid gave higher yields compared to substrates bearing 6 of 12 groups (Table 2, entries 21–26). Moreover, the optimized reaction conditions were effective for the Suzuki coupling of heteroaryl bromides with phenylboronic acids and produced products in satisfactory yields (Table 2, entries 27–32). coupling of heteroaryl bromides with phenylboronic acids and produced products in satisfactory yields (Table 2, entries 27–32). Catalysts 2018, 8, 443 electron‐withdrawing
Table 2. Suzuki coupling between aryl halides and arylboronic acids in the presence of Fe3O4@NC/Pd. a. Table 2. Suzuki coupling between aryl halides and arylboronic acids in the presence of Fe3 O4 @NC/Pd. a.
b (%) b (%) Entry Ar R Yield Entry Ar XX R Yield 96 (3a) 1 1 4‐CH 4 I I H 4-CH3O‐C H 96 (3a) 3 O-C6H 6H 4 4-NH2‐C H 96 (3b) 96 (3b) 2 2 4‐NH 6H 44 I I H 2 -C 6H 4-OH-C6H H 97 (3c) 6 H4 4 97 (3c) 3 3 4‐OH‐C I I H 4 4-CH3 -C6 H4 I H 96 (3d) 96 (3d) 4 4‐CH3‐C6H4 I H 5 4-NO2 -C6 H4 I H 99 (3e) 99 (3e) 5 6 4‐NO 2 ‐C 6 H 4 I H 4-CHO-C6 H4 I H 99 (3f) 99 (3f) 6 7 4‐CHO‐C 6H I I H 4-COCH3 -C H 98 (3g) 64H4 4-Cl-C H 97 (3h) 6 H6H 4 4 98 (3g) 7 8 4‐COCH 3‐C I I H 9 Ph I H 97 (3i) 97 (3h) 8 4‐Cl‐C6H4 I H 10 3-NO2 -C6 H4 I H 95 (3j) 97 (3i) 9 11 Ph -C H I I H 3-COCH H 94 (3k) 3 6 4 95 (3j) 10 12 3‐NO 6H 44 I I H 2-NH2‐C H 88 (3l) 2 -C 6H 13 2-CH -C H I H 86 (3m) 94 (3k) 11 3‐COCH33‐C66H44 I H 4-CH2‐C H 79 (3d) 3 -C6H 6 H4 4 88 (3l) 12 14 2‐NH I Br H 15 4-CHO-C6 H4 Br H 94 (3f) 86 (3m) 13 16 2‐CH3Ph ‐C6H4 I Br H H 94 (3i) 79 (3d) 14 17 4‐CH 6H4 BrCl H 4-NH3‐C H 53 c (3b) 2 -C6 H4 4-CHO-C66HH44 H 55 c (3f) 94 (3f) 15 18 4‐CHO‐C BrCl H 4-COCH H 57 c (3g) 94 (3i) 16 19 Ph 3 -C6 H4 BrCl H 20 Ph Cl H 56 (3i) 53 c (3b) 17 4‐NH2‐C6H4 Cl H 21 4-CH3 O-C6 H4 I 4-CHO 98 (3n) 55 c (3f) 6H4 Cl I H 4-OH 18 22 4‐CHO‐C 4-CH3 O-C 97 (3o) 6 H4 57 c (3g) 3‐C6 6H44 Cl I H 4-CH3 19 23 4‐COCH 4-CH3 O-C 97 (3p) 4-CHPh 4-F 95 (3q) 56(3i) 20 24 Cl I H 3 O-C6 H4 4-CH3O‐C 95 (3r) 3 O-C6H 6H 98 (3n) 44 I I 4‐CHO 4-Cl 21 25 4‐CH 26 4-CH3 O-C6 H4 I 3-NO2 89 (3s) 97 (3o) 22 27 4‐CH32-Py O‐C6H4 I Br 4‐OH 4-F 85 (3t) 97 (3p) 23 28 4‐CH32-Py O‐C6H4 I Br 4‐CH3 H 88 (3u) 81 (3v) 95 (3q) 24 29 4‐CH32-Py O‐C6H4 I Br 4‐F 3-NO2 30 2-quinoline Br 4-F 82 95 (3r)(3w) 25 4‐CH3O‐C6H4 I 4‐Cl 31 2-quinoline Br H 86 (3x) 89 (3s) 26 4‐CH3O‐C6H4 I 3‐NO2 32 2-quinoline Br 3-NO2 80 (3y) 85 (3t) 27 2‐Py Br 4‐F a The reaction conditions: aryl halides 1 (1 mmol), arylboronic acid 2 (1.5 mmol), Fe O @NC/Pd catalyst (10 mg), 28 2‐Py Br H 3 4 88 (3u) and KOH (1.5 mmol) in water (3 mL) under air. b Isolated yield. c 8 h. 81 (3v) 29 2‐Py Br 3‐NO2 82 (3w) 30 2‐quinoline Br 4‐F With this31 methodology in hand, we turnedBr our attention of crizotinib, which 86 (3x) 2‐quinoline H to the preparation is a potent and lymphoma kinase (c-Met/ALK) 80 (3y) 32selective Me-senchymal 2‐quinoline epithelial Br factor/anaplastic 3‐NO2 inhibitor [42]. Crizotinib has 1a (1 palladium residue problem because a The(Scheme reaction 2) conditions: aryl halides mmol), arylboronic acid 2 (1.5 mmol),the Fe3aminopyridine O4@NC/Pd coordinates to form corresponding stable compounds. As yield. a result, the separation of the c 8 h. catalystto (10palladium mg), and KOH (1.5the mmol) in water (3 mL) under air. b Isolated crizotinib API from the residual palladium has been a challenging task [43]. Thus, the coupling between aryl bromide and pinacol boronate were carried employing method. This transformation With this4methodology in hand,5we turned ourout attention to thethis preparation of crizotinib, which was accomplished with excellent results epithelial in the presence of the Fe3 O4lymphoma @NC/Pd catalyst and KOH in is a potent and selective Me‐senchymal factor/anaplastic kinase (c‐Met/ALK) ◦ C for 6 h. Then the intermediate 6 was treated with 4 M HCl in 1,4-dioxane/CH Cl , water at 90 inhibitor (Scheme 2) [42]. Crizotinib has a palladium residue problem because the aminopyridine 2 2 and the crizotinib API wastoisolated incorresponding very high yieldstable (95%)compounds. with >99% purity and 99% purity 1,4‐dioxane/CH Catalysts 2018, 8, 4432Cl2, and the crizotinib API was isolated in very high yield (95%) with >99% purity 7 of 12 and and
