Palladium-Metalated Porous Organic Polymers as Recyclable

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Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Palladium-Metalated Porous Organic Polymers as Recyclable Catalysts for the Chemioselective Synthesis of Thiazoles from Thiobenzamides and Isonitriles Wei Tong, Wen-Hao Li, Yan He, Zu-Yu Mo, Hai-Tao Tang,* Heng-Shan Wang, and Ying-Ming Pan* State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, People’s Republic of China S Supporting Information *

ABSTRACT: Two types of thiazole derivatives are synthesized through a multistep cascade sequence with Pd-metalated phosphorus-doped porous organic polymers (POPs) as heterogeneous catalysts. The POPs could be used as both ligands and catalyst supports. No obvious aggregation and loss of any catalytic activity of the catalysts were observed after 10 runs of the reaction. More importantly, imidazo[4,5-d]thiazoles, which are a new class of thiazole derivatives, could be obtained through K2CO3-promoted intramolecular cyclization of the synthesized polysubstituted thiazoles. Furthermore, the in vitro anticancer activity of these new compounds were tested with MTT assay, and compound 4b exhibited good antitumor activity toward T-24 and A549 cells with IC50 values of 10.3 ± 0.8 and 11.8 ± 0.5 μM, respectively. In addition, the action mechanism of 4b on tumor cells was determined.

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For example, a series of monophosphine or diphosphine ligandconstructed porous organic polymers were used as recyclable catalysts in hydroformylation, hydrogenation, Suzuki−Miyaura, and Heck cross-coupling reactions by Ding et al.13,14 In this study, a new Pd-metalated porous organic ligand (Pd/POLdppm)15 is reported as recyclable catalysts for the chemioselective synthesis of thiazoles from thiobenzamides and isonitriles (see Scheme 1). In order to study the structure−reactivity relationship, the prepared POL-dppm and Pd/POL-dppm were characterized with solid-state nuclear magnetic resonance (SSNMR), N2 adsorption−desorption analysis, thermogravimetry (TG), transmission electron microscopy (TEM), scanning electron microscopy (SEM), inductively coupled plasma−atomic emission spectrometry (ICP-AES), and X-ray photoelectron spectroscopy (XPS). In the 31P SSNMR spectrum of fresh Pd/ POL-dppm, the peak at 27.83 ppm is ascribed to the P atom coordinate with palladium (see Figures S1 and S2 in the Supporting Information), and the coordination of Pd(II) with POL-dppm was further confirmed by XPS (see Figure S8 in the Supporting Information). The nitrogen adsorption−desorption analysis (Figure S4 in the Supporting Information) indicates that POL-dppm and Pd/POL-dppm have large pore volumes, high surface areas, and hierarchical porosity, which is further confirmed from their SEM and TEM images (Figures S6 and S7 in the Supporting Information). According to nonlocal density functional theory (NLDFT), the pore sizes of POL-

hiazole derivatives, especially aminothiazoles, are very important in organic chemistry, because of their ubiquity in nature products,1 and wide applications in ligand chemistry,2 industrial dyes,3 and materials.4 For example, thiazolecontaining molecules often exhibit a diverse range of bioactivity including antiinflammatory, anticancer, anti-HIV, and psychotropic activities.5 In the past decade, numerous methods have been developed to prepare polysubstituted thiazoles,6−8 and one of the effective approaches involves the functionalization of substrates with the thiazole ring.7 Another more frequently used method toward polysubstituted thiazoles usually relies on the tandem intermolecular cyclization of thiobenzamides with diverse electrophiles, such as α-halocarbonyl compounds, alkynes, alkenes, and their analogues.8 In the construction of carbon−carbon bonds, palladium usually plays a significant role in the insertion of isonitriles.9 Great efforts have been made to develop homogeneous palladium catalysts with phosphine ligands, because of their high activity and selectivity. However, it is very difficult to recycle these expensive homogeneous palladium catalysts from products, compared to their corresponding heterogeneous catalysts with immobilized metal on high-surface solids.10 Because of their good chemical stability and immobile porosity, porous organic polymers (POPs) are one of the most significant classes of porous solid materials. Therefore, various POPs have been used for gas adsorption, electronics and catalysis, molecular separation and so on.11 As a new class of POPs, metalated porous organic ligands (POLs) with large pore volume, high surface area, superior stability, hierarchical porosity, and high efficiency and selectivity12 have been used as both ligands and catalyst supports for various metal catalysts. © XXXX American Chemical Society

Received: March 19, 2018

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DOI: 10.1021/acs.orglett.8b00886 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of the Reaction Conditionsa,b

Scheme 1. Synthesis of Pd/POL-dppm and Application of the Catalyst in Thiazoles Synthesis

entry

catalyst

1 2 3 4 5 6 7 8 9 10 11 12 13

Pd(PPh)4 Pd(OAc)2 PdCl2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd/POL-dppm

ligand

dppm dppe xantphos PPh3 dppm dppm dppm dppm dppm

solvent

yield (%)

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN toluene PhCl dioxane DMSO THF PhCl

20 55 trace 67 23 33 50 70 72 trace trace 23 92c

a

Reaction conditions: 1a (0.6 mmol), 2a (0.72 mmol), homogeneous catalyst (5 mol %), ligand (10 mol %), solvent (4 mL), 60 °C, 1 h. b Isolated yields. cHeterogeneous catalyst (2 mol %).

dppm and Pd/POL-dppm, were mainly distributed between 0.5 nm and 8 nm (Figure S5 in the Supporting Information). BET surface area and pore volume of POL-dppm are as high as 629.0 m2/g and 1.065 cm3/g, respectively. The BET surface area and pore volume of Pd/POL-dppm are as high as 594.8 m2/g and 0.888 cm3/g, respectively. These structural properties are very suitable for catalyst−substrate interactions. The thermogravimetry curve of POL-dppm shows that it remains intact at temperatures up to 450 °C (Figure S3 in the Supporting Information), indicating their excellent thermal stability. Furthermore, their SEM-EDS shows that all functional elements (C, P, and Pd) are highly dispersed, and the Pd/POLdppm is the perfect integration of homogeneously distributed active functional sites (see Figure 1).16 The ICP-AES analysis shows that palladium loading is 4.77 wt %.

product 3a, and dppm (10 mol %), as ligand increased the yield of 3a to 67% (Table 1, entries 4−7). Further optimization suggested that PhCl was the optimal solvent in the synthesis of thiazole 3a and the yield could be raised to 72% (Table 1, entries 8−12). In order to improve the yield of thiazole 3a further, according to the pioneering work of metalated porous organic ligands,12−14 heterogeneous catalyst Pd(OAc)2/POL-dppm was first prepared.15 The yield of 3a was improved to 92% with Pd(OAc)2/POL-dppm (2 mol %) as catalyst (Table 1, entry 13). Therefore, the optimal conditions to prepare 3a were Pd(OAc)2/POL-dppm (2 mol %) as catalyst in PhCl at 60 °C in air (Table 1, entry 13). The substrate scope for the preparation of 4,5-diaminothiazoles was examined and is depicted in Scheme 2. Thiobenzamides bearing various aromatic substituents reacted smoothly. The ortho-, meso-, and para-substitutions on the benzene ring of the thiobenzamides had no obvious effect on the product yield (see 3a−3d in Scheme 2). The thiobenzamides bearing an alkyl on the benzene ring reacted smoothly, and the corresponding products 3 were obtained in high yields (see 3b−3f in Scheme 2). Thiobenzamides bearing various substituents with diverse electronic properties at the phenyl ring (R = 4-Ph, 3-F, 3-Cl, 4-Br, 3-MeO, 3-NO2, 4OCF3) all reacted smoothly to afford the desired 4,5diaminothiazole products (see 3g−3m in Scheme 2). The thiobenzamides bearing a naphthyl or thienyl group were also tolerated (see 3n and 3o in Scheme 2). However, replacing the Ar group with an alkyl group failed to form the product 3p. In the isonitrile moiety, numerous isonitriles, including aryl isonitriles, naphthyl isonitrile, and alkyl isonitriles, were all suitable substrates, and the corresponding products were obtained in moderate to good yields (see 3q−3t in Scheme 2). The structure of product 3t is further confirmed through single-crystal X-ray structure analysis. Compound 3u, as a similar precursor of an anticancer agent,17 could also be prepared with this method. The synthetic utility of this method for 4,5-diaminothiazole 3 synthesis was illustrated through the preparation of imidazo[4,5-d]thiazoles, which is a new class of thiazole derivatives,

Figure 1. Elemental distributions in Pd/POL-dppm catalyst determined with SEM-EDS mapping: (A) SEM image, (B) carbon, (C) phosphorus, and (D) palladium.

In order to investigate the reaction conditions, thiobenzamide (1a) and isonitrile (2a) were used. When the reaction was treated with 5 mol % Pd(PPh)4 in CH3CN at 60 °C, an unexpected product thiazole 3a was obtained with 20% yield (see Table 1, entry 1). The reaction parameters were further carefully studied and the results are summarized in Table 1. Pd(OAc)2 was found to be the good homogeneous catalyst, and the yield of 3a was improved to 55% (Table 1, entries 2 and 3). Furthermore, ligands were used to improve the yield of B

DOI: 10.1021/acs.orglett.8b00886 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Synthesis of Thiazoles from Thiobenzamides with Diverse Isonitrilesa,b

Scheme 4. Synthesis of Imidazo[4,5-d]thiazoles from Thiobenzamides with Isonitrilesa,b

a

Reaction conditions: (1) 1 (0.6 mmol), 2 (0.72 mmol), heterogeneous catalyst (2 mol %), solvent (4 mL), 60 °C, 1 h. (2) K2CO3 (0.6 mmol), 75 °C. bIsolated yields.

a

Reaction conditions: 1 (0.6 mmol), 2 (0.72 mmol), heterogeneous catalyst (2 mol %), solvent (4 mL), 60 °C, 1 h. bIsolated yields.

which exhibited good antitumor activity toward T-24 and A549 cells. For example, substrate 3a worked successfully to produce the product 4a in 95% yield with stoichiometric amounts of base (see Scheme 3). Scheme 3. Synthesis of Imidazo[4,5-d]thiazoles 4a from 3a Figure 2. Recycling studies of Pd/POL-dppm.

1.37 g of 1a produced the corresponding product 3a in 87% yield. Based on the previous isocyanide insertion mechanisms9 and the TEM images,18 a plausible pathway for this reaction could be proposed (see Scheme 5). First, the coordination of

Considering the environmental friendliness and operational simplicity, we performed the two reactions in one pot (Scheme 4). After the 4,5-diaminothiazole products were observed, K2CO3 was added to the reaction mixture, and the imidazo[4,5d]thiazoles were observed in one pot through a intramolecular nucleophilic cyclization process. Therefore, substrates of a variety of thiobenzamides and isonitriles could be subjected to Pd-catalyzed intermolecular multistep cascade reactions and base-catalyzed intramolecular nucleophilic cyclization process in situ to produce 4 in good yields (see 4a−4i in Scheme 4). In order to evaluate the reusability of Pd/POL-dppm, the reaction of thiobenzamide 1a and isonitrile 2a was chosen as an example (Figure 2). After each run, the heterogeneous catalyst was recovered through filtration and washed with H2O, PhCl, acetone, and diethyl ether, and the heterogeneous catalyst could be effectively used for at least 10 cycles without losing any efficiency. During the recycling, the ICPMS analysis shows Pd species in the filtrate are undetectable (40

10.3 ± 0.8 >40

11.8 ± 0.5 >40

16.3 ± 1.5 >40

24.3 ± 2.1 >40

>40 >40

thiobenzamide 1a to Pd(II) catalyst to form the palladium species A. Next, the double insertion of isocyanide 2 into the Pd−N and Pd−S bonds produces the intermediate C, and intermediate D is generated through the intramolecular cyclization of C. Finally, the desired product 3 is obtained via an intermolecular nucleophilic addition reaction and aromatization after the elimination of a molecule of R1NH2. Product 3 further produces 4 in situ with a good yield through a basecatalyzed intramolecular nucleophilic cyclization process. According to the previous work,4b,c thiazoles usually show the unique properties of fluorescent spectra. Therefore, the properties of fluorescent spectra of products 3l and 4f were studied. The UV and fluorescent spectra were placed in the Supporting Information. The cytotoxicity of the new compound 4 was evaluated in MGC-803 (human gastric cancer), T-24 (human bladder cancer), A549 (human lung cancer), MG-63 (human osteosarcoma), SK-OV-3 (human ovarian cancer), and HUVEC (human umbilical vein endothelial) cells with the methylthiazoltetrazolium (MTT) assay and 5-fluorouracil as a positive control. The results indicated that compound 4b presented higher in vitro inhibitory activity to all cell lines than other compounds and 5-fluorouracil (5-FU). The IC50 values of compound 4b against six cell lines are shown in Table 2. Compound 4b exhibited good antitumor activity toward T-24 and A549 cells with IC50 values of 10.3 ± 0.8 and 11.8 ± 0.5 μM, respectively. In addition, according to the IC50 values of cancer cells and normal cell, these results demonstrated that compound 4b had a higher inhibitory effect on cancer cell lines than human normal cell line HUVEC (IC50 > 40 μM). Further mechanistic studies showed that compound 4b induced A549 cell apoptosis, elevated intracellular ROS levels, and decreased the mitochondrial membrane potential (see the Supporting Information for details). In summary, we have developed a highly efficient and chemoselective method to synthesize polysubstituted thiazoles through a multistep cascade sequence with highly stable and excellent reusable heterogeneous catalysts. The prepared catalysts POL-dppm and Pd/POL-dppm were fully characterized in order to study their structure−reactivity relationship. In addition, imidazo[4,5-d]thiazoles, a new class of thiazole derivatives, could be obtained through K2CO3-promoted intramolecular cyclization of the synthesized thiazole products. The in vitro anticancer activity of these new compounds were tested with MTT assay, and compound 4b exhibited good antitumor activity toward T-24 and A549 cells with IC50 values of 10.3 ± 0.8 and 11.8 ± 0.5 μM, respectively. The action mechanism of 4b on tumor cells was determined.

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Experimental procedures and characterization of compounds 3a−3u and 4a−4l (PDF) Accession Codes

CCDC 1577228 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (H.-T. Tang). *E-mail: [email protected] (Y.-M. Pan). ORCID

Hai-Tao Tang: 0000-0001-7531-0458 Heng-Shan Wang: 0000-0001-6474-8323 Ying-Ming Pan: 0000-0002-3625-7647 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (No. 21362002), Ministry of Education of China (No. IRT_16R15), Guangxi Natural Science Foundation of China (Nos. 2016GXNSFEA380001 and 2016GXNSFGA380005) and State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Nos. CMEMR2017-A02 and CMEMR2017-A07) for financial support.

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00886. D

DOI: 10.1021/acs.orglett.8b00886 Org. Lett. XXXX, XXX, XXX−XXX

Letter

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DOI: 10.1021/acs.orglett.8b00886 Org. Lett. XXXX, XXX, XXX−XXX