Palladium Complexes with Tridentate N-Heterocyclic Carbene

Article pubs.acs.org/Organometallics

Palladium Complexes with Tridentate N‑Heterocyclic Carbene Ligands: Selective “Normal” and “Abnormal” Bindings and Their Anticancer Activities Jing-Yi Lee,† Jhen-Yi Lee,† Yuan-Yu Chang,† Ching-Han Hu,† Nancy M. Wang,*,‡ and Hon Man Lee*,† †

Department of Chemistry and ‡Graduate Institute of Biotechnology, National Changhua University of Education, Changhua 50058, Taiwan, Republic of China

Downloaded by FLORIDA ATLANTIC UNIV on August 29, 2015 | http://pubs.acs.org Publication Date (Web): August 28, 2015 | doi: 10.1021/acs.organomet.5b00586

S Supporting Information *

ABSTRACT: A series of new imidazolium salts was synthesized by simple quaternization reactions of 1-benzyl-1Himidazole or 1-benzyl-2-methyl-1H-imidazole and their derivatives with 2-chloro-N-(pyridin-2-ylmethyl)acetamide. These resulting imidazolium salts were successfully employed as ligand precursors for the syntheses of novel palladium(II) complexes bearing tridentate ligands of N-heterocyclic carbene, amidate, and pyridine donor moieties. Simple tuning of the reaction conditions allowed selective coordination of the Nheterocyclic carbene moiety in either “normal” or “abnormal” binding modes. An isomeric pair of palladium complexes with “normal” and “abnormal” N-heterocyclic carbenes was successfully characterized by single-crystal X-ray diffraction studies. Theoretical calculations indicated that the palladium complex with “normal” NHC coordination was more thermally stable than its isomeric complex with “abnormal” NHC binding. The potential of these two sets of palladium complexes as anticancer drugs was evaluated, and the results showed that some of these novel complexes exhibited promising inhibition activity against human ovarian cancer cell lines. The inhibition activity of these novel complexes was highly structurally dependent. While the nNHC complex bearing an N-3-methoxybenzyl group appeared to be the most active compound, its isomeric aNHC complex did not exhibit any inhibition activity toward TOV21G cells. In contrast, in the case of an isomeric pair of palladium complexes bearing N-4-fluorobenzyl groups, the aNHC complex showed activity superior to that of the nNHC complex.

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INTRODUCTION Cisplatin, carboplatin, and oxaliplatin are proven anticancer drugs used worldwide for the treatment of a range of cancers.1 However, a limited spectrum of activity, high toxicity, drug resistance, and serious side effects arising from the covalent interaction of platinum with DNA2 have prompted the development of alternative metal-based anticancer drugs.3 Palladium(II) complexes, in particular, show considerable promise due to their structural and chemical similarities with platinum(II) compounds.3a However, Pd−ligand bonds are considerably more labile than their Pt−ligand counterparts. It has been shown that both preventing possible cis−trans isomerization and slowing the rate of dissociation or hydrolysis of palladium(II) complexes are crucial in aiding their reactive species to reach their pharmacological targets.3a Thus, the stabilization of palladium(II) complexes by strong M−N/M−C bonds or the formation of cyclometalated structures is desirable for palladium-based anticancer complexes. N-heterocyclic carbenes (NHCs) have recently attracted a considerable amount of interest because of their accessibility, high thermal stability, and the remarkable catalytic activities of their transition-metal complexes in diverse organic transformations.4 Recently, metal NHC complexes have also been © XXXX American Chemical Society

exploited in therapeutic applications, including anticancer reagents.3b−g,5,6 Ghosh et al. reported the palladium(II) NHC complex [1-benzyl-3-tert-butylimidazol-2-ylidene]2PdCl2, which exhibited a strong antiproliferative activity against human tumor cells of cervical cancer (HeLa), breast cancer (MCF-7), and colon adenocarcinoma (HCT 116).6 We envisioned that new palladium(II) complexes bearing tridentate ligands consisting of NHC, amidate, and pyridine donor moieties may have potential as active anticancer complexes because they feature strong M− C and M−N bonds through the coordination of carbene and amidate moieties and also because the resulting cyclometalated rings impart high stability to the complexes. This new ligand system also contains a terminal pyridyl moiety, which is crucial for controlling the sites of deprotonation and thus the subsequent palladation (Chart 1). As reported by us previously, in the absence of this pyridine coordination, products other than NHC complexes could be formed.7 Also, the pyridine coordination should be labile, allowing the target palladium(II) NHC complexes to possess a reasonable degree of hemilability for subsequent substrate binding. In addition, imidazole-based Received: July 9, 2015

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DOI: 10.1021/acs.organomet.5b00586 Organometallics XXXX, XXX, XXX−XXX

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Organometallics


Chart 1. Design of Ligand Precursors for the Formation of Different Palladium Complexesa

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Asterisks (*) denote possible sites of deprotonation.

Scheme 1. Synthesis of Imidazolium Salts

derivatives that could be employed as precursors for the preparation of Pd(II) complexes with targeted tridentate ligands. Optimization of the reaction conditions was conducted, allowing us to selectively prepare palladium complexes with NHCs of either “normal” or “abnormal” coordination modes. The potential of these two sets of isomeric complexes as anticancer drugs was also evaluated. Our results indicated that these novel complexes could exhibit promising inhibition activity against human ovarian cancer cell lines.

NHC ligands could possess an alternative binding mode via the C4/5 atoms, rather than the C2 atom in the imidazolium ring.8 Such “abnormal” NHC (aNHC) ligands have attracted a significant amount of attention because metal aNHC complexes have unique properties in comparison to their “normal” NHC (nNHC) counterparts.9,10 Both experimental11,12 and theoretical calculations13 have demonstrated that aNHCs are stronger σ-donors than their isomeric counterparts, nNHCs. Comparative studies on the catalytic properties of isomeric transitionmetal complexes of nNHC and aNHC ligands have also received a significant amount of attention.11,14 Despite the great potential of Pd(II) complexes bearing NHC ligands for application as anticancer drugs,6 to the best of our knowledge, comparative studies on the cytotoxicities of isomeric palladium nNHC and aNHC complexes have not yet been exploited. We herein report the preparation of a series of novel imidazole

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RESULTS AND DISCUSSION Synthesis of Ligand Precursors. Quaternization reactions of 2-chloro-N-(pyridin-2-ylmethyl)acetamide with 1-benzyl1H-imidazole (1aa) and its derivatives (1ab−ac) in ethanol at 75 °C for 5 h yielded the imidazolium chlorides 2aa−ac, which were potential ligand precursors for the formation of B


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Organometallics

absence of downfield NH and NCHN resonances at ca. 9.7 and 10.1 ppm, respectively, in the 1H NMR spectra indicated the successful complexation of the chelating NHC ligands. In addition, the 13C{1H} NMR spectrum provided supporting evidence that the NHC coordinated in a “normal” manner, as the carbenic carbon signals in 3a−c were observed at ca. 153.5 ppm. This chemical shift is comparable to those reported for Pd(II) complexes with trans monodentate nNHC and pyridine ligands (ca. 151 ppm).15 Palladium nNHC complexes could not be formed when ligand precursors 2ba−bc without NCHN protons were employed. In this case, deprotonation could took place at the C4 or C5 position, leading to the possible formation of palladium aNHC complexes. It could be anticipated that deprotonation at the C5 carbon would take place preferentially due to the possible formation of a stable tridentate chelate. However, when the same conditions were employed for nNHC complexes 3a−c, the reactions failed to deliver the desired palladium aNHC complexes. Pleasingly, an increase in the reaction temperature to 50 °C resulted in the formation of complexes 4a−c, which were isolated as white solids in 30− 51% yields (Scheme 3). As was the case for nNHC complexes 3a−c, these complexes were stable in air and displayed good solubility in organic solvents. All complexes were characterized by means of NMR spectroscopy, elemental analysis, and in the case of 4b single-crystal X-ray diffraction analysis. As previously mentioned, the carbene resonances for the nNHC complexes 3a−c were observed in the 13C{1H} NMR spectra at ca. 153.5 ppm. In contrast, the characteristic “abnormal” carbenic carbon resonances of the aNHC complexes 4a−c were observed at 136.0, 130.1, and 130.4 ppm, respectively. These upfield chemical resonances were comparable to those reported in monodentate palladium complexes with trans aNHC and pyridine ligands.14a The blocking of normal binding by installing a methyl group on the C2 position on the ligand precursors was a viable method for the formation of complexes with aNHCs (see Scheme 3).16 However, this strategy may be somewhat limited by the availability of starting materials or the requirement of additional synthetic steps. It has been shown in the literature that alternative sites of C−H activation may occur, other than at the C4/5 position of the ligand precursors, leading to the possible formation of products other than aNHC complexes (see Chart 1).7 Hence, it would be desirable to achieve the selective formation of palladium complexes with either “normal” or “abnormal” NHC coordination from common ligand precursors. Typically, however, deprotonation occurs more favorably at the C2 carbon, leading to the nNHC complexes, as in the case of complexes 3a−c in Scheme 2. In fact, the difficulty in achieving selective NHC binding was reflected in the literature, where in the preparation of metal

tridentate ligands of NHC, amidate, and pyridine donor moieties (Scheme 1). Moderate to good product yields (60− 87%) were obtained in all cases. The new imidazolium salts were characterized by NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS). Characteristic downfield signals for NH and NCHN protons in 2aa−ac were observed in their 1H NMR spectrum at ca. 9.7 and 10.1 ppm, respectively. Their ESI-MS spectra exhibited base peaks corresponding to the [M − Cl]+ imidazolium cations. The formation of palladium complexes with “normal” NHC coordination could be prevented by replacing the acidic proton on the C2 atom with a methyl group in 2aa−ac. The inaccessibility of C2 coordination opens up the possibility of formation of Pd−C bonds via C4/5 atoms, affording metal complexes of aNHCs. Imidazolium derivatives 2ba−bc bearing methyl groups on the C2 atoms were therefore prepared. A procedure similar to the preparation of 2aa−ac was employed, but using 1-benzyl-2-methyl-1H-imidazole (1ba) and its derivatives (1bb,bc) rather than 1-benzyl-1H-imidazole (1aa) and its derivatives (1ab,ac). Pure products 2ba−bc with yields in the range of 47−83% were obtained. Noticeably in the 1H NMR spectra of these products, the NH signals observed at ca. 9.8 ppm for 2ba−bc were shifted ca. 0.1 ppm downfield in comparison to those for 2aa−ac. Again, ESI-MS analyses confirmed the successful preparation of these ligand precursors, with base peaks due to the [M − Cl]+ imidazolium cations being observed in their spectra. All novel imidazolium salts prepared were highly hygroscopic and were therefore stored and handled in a glovebox. Synthesis of Palladium nNHC and aNHC Complexes. Palladium nNHC complexes 3a−c were prepared by reacting the ligand precursors 2aa−ac with PdCl2 in DMF in the presence of K2CO3 as base at room temperature overnight (Scheme 2), giving the desired products as yellow solids. Scheme 2. Synthesis of Palladium nNHC Complexes

Complexes 3a,c were obtained in good yields of 66 and 68%, respectively, while 3b was isolated in only 28% yield. These new complexes were found to be air stable and exhibited good solubility in halogenated organic solvents. All complexes were characterized by NMR spectroscopy, elemental analysis, and in the case of 3a single-crystal X-ray diffraction analysis. The Scheme 3. Synthesis of Palladium aNHC Complexes

C


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Scheme 4. Selective Synthesis of Palladium aNHC Complexes

was also found to be significantly lower in energy than the aNHC isomer 3a′, with free energy differences of 9.2 and 11.2 kcal/mol using the B3LYP and M06 density functionals, respectively. Our computational results were in agreement with those reported by Barnard et al.,17 who demonstrated that nNHC/nNHC coordination modes were significantly more thermodynamically stable than the aNHC/aNHC coordination modes in nickel(II) and palladium(II) complexes with bisNHC ligands. The formation of aNHC complex 3a′ instead of the thermodynamically more stable nNHC complex 3a in Scheme 4 could be explained by the fact that the acetate anion from Pd(OAc)2 and NaOAc facilitated deprotonation at the C5 position, leading to the formation of complex 3a′ as the kinetic product. It therefore appeared that deprotonation of the C5 atoms on 2aa−ac was closely related to the palladium-catalyzed C5-direct arylation of 1-methylimidazole with aryl halides, in which the C−H activation and subsequent palladation occurred at the C5 atom (Scheme 5).21 A concerted metalation−

aNHC complexes from ligand precursors with unblocked C2 position a mixture of nNHC and aNHC complexes was generally obtained.16,17 Controlled deprotonation at the C2 or C4/5 positions on the imidazolium ligand precursors, therefore, remains a challenge. Interestingly, we found that palladium aNHC complexes 3a′−c′ could be formed exclusively from the imidzolium precursors 2aa−ac using Pd(OAc)2 and NaOAc, in place of PdCl2 and K2CO3 as the palladium precursor and base, respectively. Thus, when the reaction mixture was stirred at room temperature overnight, pure complexes 3a′−c′ were obtained in 38−62% yields. Their stability and solubility were similar to those of their isomeric nNHC complexes 3a−c. These new complexes were characterized by both NMR spectroscopy and elemental analysis. In the case of 3a′, the structure was further established by single-crystal X-ray diffraction studies. A comparison of the 13C{1H} NMR spectra of isomeric 3a and 3a′ clearly showed that, in the spectrum of aNHC complex 3a′, the “normal” carbene resonance at ca. 153.5 ppm was absent (see Figure S1 in the Supporting Information). Instead, two signals at 132.9 and 134.2 ppm were observed, likely corresponding to the “abnormal” carbene resonance. A distortionless enhancement by polarization transfer (DEPT) experiment indicated that the two signals were from quaternary and CH carbons, respectively (see Figure S10 in the Supporting Information). A heteronuclear multiplebond correlation (HMBC) experiment subsequently confirmed that the resonance at 132.9 ppm was due to the carbenic carbon (see Figure S11 in the Supporting Information). In addition, the “abnormal” carbene resonances normally observed at 132.9, 132.8, and 135.3 ppm were shifted ca. 20 ppm upfield in comparison to the “normal” carbene signals of their isomeric complexes 3a−c (ca. 153.5 ppm). It is worth noting that, while the melting points for 3a−c and 3a′−c′ were in the range of ca. 151−169 °C, those for 4b,c were much higher and were in the range of ca. 262−298 °C. Apparently, all of these complexes did not decompose at their melting temperatures. These complexes also exhibited high stability in phosphate-buffered saline (PBS). For example, after a suspension complex 3b was stirred in PBS for 2 h, it remained intact according to 1H NMR spectroscopy. To gain a better understanding of the relative stabilities of the isomeric nNHC and aNHC complexes, the free energies of 3a and 3a′ at 298 K were computed using density functional theory (DFT). The geometries of 3a and 3a′ were optimized using B3LYP18,19 and M0620 functionals. The calculated bond distances were found to be close to those of structures from single-crystal X-ray diffraction studies, suggesting validation of the computational method (Table S2 in the Supporting Information). It should be noted that both the structural and calculated data indicated that the Pd−C bond distance of the palladium nNHC complex 3a was longer than that of its isomer 3a′ bearing an aNHC ligand. The Pd(II) nNHC complex 3a

Scheme 5. Palladium-Catalyzed Direct Arylation of 1Methyimidazole

deprotonation (CMD) pathway in which the carboxylate, pivalate (PivO−) in this case, serves as the soluble base was proposed as the mechanism for this reaction.22 Given the structural similarities of the starting materials and the similar reaction conditions employed, a chelation-assisted CMD pathway for the palladation of imidazolium salts 2aa−ac to give aNHCs complexes 3a′−c′ was proposed (Scheme 6). In this CMD pathway, chelate complex A with π coordination of the imidazolyl ring was formed initially. The aNHC complexes were then formed following an acetate-assisted C−H activation step, the release of acetic acid, and chloride coordination. In contrast, the use of K2CO3 as base led to deprotonation of the acidic H atom at the C2 position of 2aa−ac. The in situ generated free carbene was trapped by PdCl2, leading to the formation of nNHC complexes 3a−c. Molecular Structures. Crystals of 3a, 3a′, and 4b suitable for X-ray diffraction studies were obtained from vapor diffusion of n-hexane into a dichloromethane solution containing the palladium complexes. Crystallographic data are given in Table S1 in the Supporting Information, while selected bond distances and angles are given in Table 1. Structural determination confirmed the tridentate coordination mode of the nNHC and aNHC ligands in these complexes (Figures 1 and 2). In general, the palladium centers in the three structures D


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Scheme 6. Mechanistic Proposal for the Formation of aNHC and nNHC Complexes

Table 1. Selected Bond Distances (Å) and Angles (deg) around Pd in 3a, 3a′, and 4b 3a Pd1−C1 Pd1−Cl1 Pd1−N3 Pd1−N4 C1−Pd1−Cl1 C1−Pd1−N4 N3−Pd1−N4 N3−Pd1−Cl1 C1−Pd1−N3 N4−Pd1−Cl1

3a′ 1.992(10) 2.311(2) 2.046(8) 1.986(7) 95.9(3) 88.1(3) 81.6(3) 94.6(2) 169.2(3) 173.5(2)

Pd1−C2 Pd1−Cl1 Pd1−N3 Pd1−N4 C2−Pd1−Cl1 C2−Pd1−N4 N3−Pd1−N4 N3−Pd1−Cl1 C2−Pd1−N3 N4−Pd1−Cl1

4b 1.959(3) 2.3133(7) 2.084(2) 1.992(2) 90.06(8) 93.01(10) 81.72(9) 95.39(7) 173.64(10) 175.89(7)

Pd1−C9 Pd1−Cl1 Pd1−N3 Pd1−N4 C9−Pd1−Cl1 C9−Pd1−N4 N3−Pd1−N4 N3−Pd1−Cl1 C9−Pd1−N3 N4−Pd1−Cl1

1.965(3) 2.3275(9) 2.090(3) 1.975(3) 91.03(11) 92.31(13) 81.87(12) 94.97(9) 173.40(13) 175.26(8)

Figure 1. Molecular structures of 3a and 3a′ with 50% probability ellipsoids. H atoms are omitted for clarity.

1.965(3) Å in the aNHC complex 4b was comparable to that of 3a′. The Pd−C bond distances in aNHC complexes 3a′ and 4b were comparable to those in monodentate palladium(II) complexes bearing aNHC and pyridine ligands.14a Due to the stronger trans influence of the aNHC moiety in complex 3a′, its trans Pd1−N3 bond distance of 2.084(2) Å was longer than that of the nNHC complex 3a (2.046(8) Å). Furthermore, the Pd1−Cl1 (2.311(2) and 2.3133(7) Å) and Pd1−N4 (1.986(7) and 1.992(2) Å) bond distances in complexes 3a and 3a′ were found to be similar. Finally, due to strong amidate coordination, the Pd−N bond distances from the amidate groups (1.975(3)− 1.992(2) Å) were markedly shorter than those from the pyridine groups (2.046(8)−2.090(3) Å). Cytotoxicity. The anticancer activities of all novel palladium complexes bearing nNHC and aNHC ligands were evaluated against three types of human tumor cells: namely, ovarian cancer (TOV21G), colon adenocarcinoma (SW620),

Figure 2. Molecular structure of 4b with 50% probability ellipsoids. H atoms are omitted for clarity.

were found to adopt a distorted-square-planar geometry. In the isomeric nNHC and aNHC complexes 3a and 3a′, the Pd−C bond in the latter complex was significantly shorter (1.992(10) vs 1.959(3) Å), reflecting the stronger electron donating property of the aNHC moiety. In addition, a Pd−C distance of E


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IC50 values of 17.78 and 49.55 μM being recorded. On the other hand, the series of aNHC complexes 4a−c did indeed exhibit inhibition activity. After complex 3b, 4a, bearing a methyl group on the NCN carbon atom of its aNHC framework and an N-benzyl group, was found to be the most active complex in arresting the growth of TOV21G cells. However, the IC50 value of 4a was 12.78 μM, double that of 3b. Finally, to determine the inhibition activity of our novel compounds with respect to that of current clinical anticancer drugs, the IC50 value of cisplatin toward TOV21G cells was determined and was found to be 4.980 μM. Therefore, the comparable IC50 values of 3b and cisplatin clearly reflect the enormous potential of this palladium nNHC compound as an anticancer drug. The activity of 3b was also comparable to that exhibited by the Pd nNHC complex trans-[1-benzyl-3-tertbutylimidazol-2-ylidene]2PdCl2, reported by Ghosh et al.6a The reported complex had a strong inhibition effect against three types of human tumor cells in culture: namely, cervical cancer (HeLa), breast cancer (MCF-7), and colon adenocarcinoma (HCT 116). Their IC50 values were 4, 1, and 0.8 μM, respectively. Furthermore, our preliminary studies showed that these complexes may inhibit tumor cell proliferation by binding to DNA and lead to cell cycle arrest. Since structural modifications of these complexes may reduce the incidence of toxic side effects, pharmacokinetic and toxicity studies of these potential drugs are currently being carried out.

and small-cell lung carcinoma (NCI-H1688) (Table 2). All of the compounds were solubilized at 100 mM in DMSO and


Table 2. Comparison of IC50 Values of Palladium(II) Compounds and Cisplatin

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CONCLUSIONS A novel series of imidazolium salts was designed and successfully used for the preparation of palladium(II) complexes with tridentate ligands of NHC, amidate, and pyridine donor moieties. Mild reaction conditions were discovered, allowing the selective preparation of isomeric palladium(II) complexes with either “normal” or “abnormal” NHC ligands from the same imidazolium ligand precursors at room temperature. The selective formation of aNHC complexes employing Pd(OAc)2 and NaOAc as the metal precursor and base, respectively, could be explained by a chelation-assisted CMD pathway in which the acetate served as an intramolecular base for the deprotonation step. The anticancer activity of these complexes was tested, and it was found that one of the novel isomeric palladium nNHC complexes exhibited an IC50 value comparable to that of cisplatin and could therefore be considered a potential anticancer drug for the treatment of human ovarian cancer. In addition, it was found that the inhibition activity of these novel complexes was highly structurally dependent. While the nNHC complex 3b bearing an N-3-methoxybenzyl group appeared to be the most active compound, its isomeric aNHC complex 3b′ did not exhibit any inhibition activity toward TOV21G cells. In contrast, in the case of isomeric palladium complexes 3c and 3c′ bearing N-4-fluorobenzyl groups, the aNHC complex 3c′ showed activity superior to that of the nNHC complex 3c. Further animal tests for the most active complex are currently ongoing to better understand its anticancer and chemotherapeutic activity in vivo.

a

Amount of compounds necessary to arrest the growth of human ovarian cancer (TOV21G), colon adenocarcinoma (SW620), and small-cell lung carcinoma cells (NCI-H1688) by 50% in 48 h. Data are the averages of three independent runs.

further diluted in serum-free DMEM without precipitation out of solution. Following a 48 h exposure of the palladium compounds to the cancer cell lines, an MTT assay was conducted to assess the cytotoxicity of each complex. Among the three cell lines tested, our palladium complexes were found to be more effective in the inhibition of TOV21G cells, although aNHC complexes 3a′ and 3b′ were ineffective in the inhibition of this cancer cell line. In addition, the palladium nNHC complex 3b, bearing an N-3-methoxybenzyl group, was the most active compound against all three cell lines and, in particular, exhibited high selectivity toward TOV21G cells with a half maximal inhibitory concentration (IC50) of 6.050 μM. It should be noted that we found the inhibition activity to be highly dependent on the structures of the palladium complexes. While the nNHC complex 3b appeared to be the most active compound, its isomeric aNHC complex 3b′ did not exhibit any inhibition activity toward TOV21G cells. Replacing the N-3methoxy group in 3b with an H or 4-F atom led to poorer activities with significantly higher IC50 values of 23.44 and 49.55 μM, respectively (3b → 3a,c). In contrast to the case of the isomeric pair of 3b and 3b′, the activity of aNHC complex 3c′ was higher than that of its isomeric nNHC complex 3c, with

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EXPERIMENTAL SECTION

General Considerations. All manipulations were performed under a dry nitrogen atmosphere using standard Schlenk techniques. Unless otherwise noted, all catalytic reactions were carried out in thickwalled sealable tubes. All of the solvents were directly used as received without any further purification unless otherwise specified. Common

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Organometallics

(d, 1H, 3J(HH) = 3.0 Hz, Ar H), 8.44 (d, 1H, 3J(HH) = 3.0 Hz, Py H), 9.84 (t, 1H, 3J(HH) = 6.0 Hz, NH). 13C{1H} NMR (CDCl3): δ 10.9 (CH3), 44.9 (CH2), 50.9 (CH2), 52.3 (CH2), 121.1 (CH), 121.8 (CH), 122.3 (CH), 123.2 (CH), 127.4 (CH), 127.9 (CH), 129.6 (CH), 132.3 (quaternary C), 137.3 (CH), 145.4 (NCN), 148.7 (CH), 157.2 (quaternary C), 165.5 (CO). HRMS (ESI): m/z calcd for C19H21N4O [M − Cl]+ 321.1710, found 321.1707. Synthesis of [C20H23N4O2]Cl (2bb). The compound was prepared by a procedure similar to that for 2aa. A mixture of 2-chloro-N(pyridin-2-ylmethyl)acetamide (1.07 g, 5.79 mmol) and 1-(3methoxybenzyl)-2-methyl-1H-imidazole (1.40 g, 6.95 mmol) was used. A yellow solid was obtained. Yield: 1.86 g (83%). 1H NMR (CDCl3): δ 2.73 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 4.53 (d, 2H, 2 J(HH) = 6.0 Hz, CH2), 5.27 (s, 2H, CH2), 5.45 (s, 2H, CH2), 6.65− 6.87 (m, 3H, Ar H), 7.06−7.40 (m, 4H, Ar H), 7.60 (t, 1H, 3J(HH) = 6.0 Hz, Ar H), 7.72 (d, 1H, 3J(HH) = 3.0 Hz, Ar H), 8.42 (d, 1H, 3 J(HH) = 6.0 Hz, Py H), 9.89 (t, 1H, 3J(HH) = 3.0 Hz, NH). 13C{1H} NMR (CDCl3): δ 10.5 (CH3), 44.6 (CH2), 50.5 (CH2), 51.8 (CH2), 55.3 (OCH3), 113.5 (CH), 114.1 (CH), 119.7 (CH), 121.4 (CH), 121.7 (CH), 122.3 (CH), 122.9 (CH), 130.4 (CH), 134.3 (quaternary C), 137.4 (CH), 145.3 (NCN), 148.3 (CH), 156.9 (quaternary C), 159.9 (quaternary C), 165.3 (CO). HRMS (ESI): m/z calcd for C20H23N4O2 [M − Cl]+ 351.1816, found 351.1822. Synthesis of [C19H20N4OF]Cl (2bc). The compound was prepared by a procedure similar to that for 2aa. A mixture of 2-chloro-N(pyridin-2-ylmethyl)acetamide (0.84 g, 4.55 mmol) and 1-(4fluorobenzyl)-2-methyl-1H-imidazole (1.29 g, 6.83 mmol) was used. A yellow solid was obtained. Yield: 0.80 g (47%). 1H NMR (CDCl3): δ 2.73 (s, 3H, CH3), 4.55 (d, 2H, 2J(HH) = 6.0 Hz, CH2), 5.35 (s, 2H, CH2), 5.44 (s, 2H, CH2), 7.00−7.28 (m, 6H, Ar H), 7.43 (d, 1H, 3 J(HH) = 9.0 Hz, Ar H), 7.63−7.72 (m, 2H, Ar H), 8.43 (d, 1H, 3 J(HH) = 6.0 Hz, Py H), 9.81 (t, 1H, 3J(HH) = 6.0 Hz, NH). 13C{1H} NMR (CDCl3): δ 10.9 (CH3), 44.5 (CH2), 50.8 (CH2), 51.5 (CH2), 116.5 (d, 2J(CF) = 21.8 Hz, Ar C), 121.0 (CH), 122.1 (CH), 122.6 (CH) 123.2 (CH), 128.5 (quaternary C), 130.1 (d, 3J(CF) = 9.0 Hz, Ar C), 138.0 (CH), 145.5 (NCN), 148.0 (CH), 156.8 (quaternary C), 162.9 (d, 1J (CF) = 249.1 Hz, CF), 165.4 (CO). HRMS (ESI): m/z calcd for C19H20N4OF [M − Cl]+ 339.1616, found 339.1627. Synthesis of C18H17ClN4OPd (3a). In a 20 mL Schlenk flask were dissolved PdCl2 (0.066 g, 0.37 mmol), 2aa (0.128 g, 0.37 mmol), and K2CO3 (0.206 g, 1.49 mmol) in dry DMF (10 mL) under a nitrogen atmosphere. The solution was stirred at room temperature overnight. The residue was washed with water and extracted with DCM twice. The extract was dried over anhydrous MgSO4 and evaporated to dryness under vacuum to give a solid. Diethyl ether was added, and the yellow solid that formed was collected on a frit and dried under vacuum. Yield: 0.112 g (66%). Mp: 168.3−168.8 °C. Anal. Calcd for C18H17ClN4OPd: C, 48.34; H, 3.83; N, 12.52. Found: C, 48.68; H, 4.08; N, 12.31. 1H NMR (d6-DMSO): δ 4.74 (s, 2H, COCH2), 5.10 (s, 2H, PyCH2), 5.15 (s, 2H, NCH2Ph), 7.26−7.28 (m, 4H, Ar H), 7.39− 7.45 (m, 4H, Ar H), 7.77−7.85 (m, 2H, Ar H), 9.00 (d, 1H, 3J(HH) = 6.0 Hz, Py H). 13C{1H} NMR (CDCl3): δ 54.4 (CH2), 56.4 (CH2), 57.1 (CH2), 120.5 (CH), 121.4 (CH), 122.1 (CH), 122.4 (CH), 128.2 (CH), 128.9 (CH), 136.2 (quaternary C), 138.7 (CH), 147.9 (CH), 153.5 (Pd−C), 164.1 (quaternary C), 166.5 (CO). Synthesis of C19H19ClN4O2Pd (3b). The compound was prepared by a procedure similar to that for 3a. A mixture of PdCl2 (0.076 g, 0.43 mmol), 2ab (0.161 g, 0.43 mmol), and K2CO3 (0.239 g, 1.73 mmol) was used. A yellow solid was obtained. Yield: 0.057 g (28%). Mp: 168.8−169.2 °C. Anal. Calcd for C19H19ClN4O2Pd: C, 47.81; H, 4.01; N, 11.73. Found: C, 48.26; H, 4.14; N, 11.83%. 1H NMR (CDCl3): δ 3.80 (s, 3H, CH3), 4.71 (s, 2H, CH2), 5.07 (s, 4H, CH2), 6.76−6.94 (m, 3H, Ar H), 7.22−7.38 (m, 4H, Ar H), 7.77−7.79 (m, 2H, Ar H), 8.97 (d, 1H, 3J(HH) = 6.0 Hz, Py H). 13C{1H} NMR (CDCl3): δ 54.3 (CH2), 55.2 (OCH3), 56.3 (CH2), 57.1 (CH2), 113.8 (CH), 113.9 (CH), 120.5 (CH), 121.4 (CH), 122.1 (CH), 122.4 (CH), 129.9 (CH), 137.7 (quaternary C), 138.7 (CH), 147.9 (CH), 153.4 (Pd−C), 159.9 (quaternary C), 164.0 (quaternary C), 166.5 (CO).

starting chemicals were purchased from commercial sources and used as received. 1H and 13C{1H} NMR spectra, unless otherwise specified, were recorded at 300.13 and 75.47 MHz, respectively. CDCl3 and d6DMSO as solvents and tetramethylsilane (TMS) as the internal standard were employed. Chemical shifts are reported in units (ppm) by assigning the TMS resonance in the 1H NMR spectrum as 0.00 ppm. The 1H NMR data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, and br = broad), coupling constant (J value) in Hz, and integration. Chemical shifts for 13C{1H} NMR spectra were recorded in ppm using the central peak of CDCl3 (77.0 ppm) or d6-DMSO (39.5 ppm) as the internal standard. Flash chromatography was performed using 230− 400 mesh silica gel. ESI-MS was carried out on a sector field mass spectrometer. Elemental analysis was performed on a CHN-O elemental analyzer. ESI-MS was carried out on a sector field mass spectrometer. 2-Chloro-N-(pyridin-2-ylmethyl)acetamide was prepared according to a literature procedure.23 Synthesis of [C18H19N4O]Cl (2aa). A mixture of 2-chloro-N(pyridin-2-ylmethyl)acetamide (1.20 g, 6.52 mmol) and 1-benzyl-1Himidazole (1.23 g, 7.82 mmol) in EtOH (25 mL) was placed in a Schlenk flask. The mixture was heated at reflux for 5 h. After cooling and then washing with THF, the yellow solid was collected on a frit and dried under vacuum. Yield: 1.53 g (69%). 1H NMR (CDCl3): δ 4.52 (d, 2H, 2J(HH) = 6.0 Hz, CH2), 5.40 (s, 2H, CH2), 5.46 (s, 2H, CH2), 7.06−7.09 (m, 2H, Ar H), 7.33−7.37 (m, 6H, Ar H), 7.55−7.60 (m, 2H, Ar H), 8.39 (d, 1H, 3J(HH) = 6.0 Hz, Py H), 9.69 (s, 1H, NH), 10.06 (s, 1H, NCHN). 13C{1H} NMR (CDCl3): δ 44.3 (CH2), 51.6 (CH2), 53.2 (CH2), 121.1 (CH), 122.3 (CH), 122.7 (CH), 124.1 (CH), 128.7 (CH), 129.3 (CH), 132.8 (quaternary C), 137.5 (NCHN), 138.4 (CH), 147.5 (CH), 156.3 (quaternary C), 165.5 (CO). HRMS (ESI): m/z calcd for C18H19N4O [M − Cl]+ 307.1553, found 307.1550. Synthesis of [C19H21N4O2]Cl (2ab). The compound was prepared by a procedure similar to that for 2aa. A mixture of 2-chloro-N(pyridin-2-ylmethyl)acetamide (1.23 g, 6.69 mmol) and 1-(3methoxybenzyl)-1H-imidazole (1.51 g, 8.03 mmol) was used. A yellow solid was obtained. Yield: 2.17 g (87%). 1H NMR (CDCl3): δ 3.69 (s, 3H, OCH3), 4.52 (d, 2H, 2J(HH) = 6.0 Hz, CH2), 5.37 (s, 2H, CH2), 5.45 (s, 2H, CH2), 6.79−6.87 (m, 3H, Ar H), 7.10−7.22 (m, 3H, Ar H), 7.42−7.66 (m, 3H, Ar H), 8.39 (d, 1H, 3J(HH) = 3.0 Hz, Py H), 9.76 (s, 1H, NH), 10.00 (s, 1H, NCHN). 13C{1H} NMR (CDCl3): δ 44.3 (CH2), 51.7 (CH2), 53.3 (CH2), 55.4 (OCH3), 114.4 (CH), 114.9 (CH), 120.8 (CH), 121.0 (CH), 122.3 (CH), 122.7 (CH), 124.1 (CH), 130.5 (CH), 134.1 (NCHN), 137.6 (CH), 138.4 (CH), 147.5 (CH), 156.6 (quaternary C), 160.1 (quaternary C), 165.5 (CO). HRMS (ESI): m/z calcd for C19H21N4O2 [M − Cl]+ 337.1659, found 337.1654. Synthesis of [C18H18N4OF]Cl (2ac). The compound was prepared by a procedure similar to that for 2aa. A mixture of 2-chloro-N(pyridin-2-ylmethyl)acetamide (1.05 g, 5.69 mmol) and 1-(4fluorobenzyl)-1H-imidazole (1.20 g, 6.83 mmol) was used. A yellow solid was obtained. Yield: 1.25 g (60%). 1H NMR (CDCl3): δ 4.53 (d, 2H, 2J(HH) = 6.0 Hz, CH2), 5.43 (s, 2H, CH2), 5.46 (s, 2H, CH2), 6.95−7.13 (m, 4H, Ar H), 7.35−7.41 (m, 3H, Ar H), 7.58−7.64 (m, 2H, Ar H), 8.41 (d, 1H, 3J(HH) = 3.0 Hz, Py H), 9.62 (s, 1H, NH), 10.12 (t, 1H, 4J(HH) = 6.0 Hz, NCHN). 13C{1H} NMR (d6-DMSO): δ 44.4 (CH2), 51.2 (CH2), 51.4 (CH2), 116.2 (d, 2J(CF) = 20.4 Hz, CH), 122.0 (CH), 122.2 (CH), 123.0 (CH), 124.7 (CH), 131.3 (d, 3 J(CF) = 9.0 Hz, CH), 131.6 (quaternary C), 137.9 (NCHN), 138.1 (CH), 148.5 (CH), 157.8 (quaternary C), 162.6 (d, 1J(CF) = 241.5 Hz, CF), 165.8 (CO). HRMS (ESI): m/z calcd for C18H18N4OF [M − Cl]+ 325.1459, found 325.1456. Synthesis of [C19H21N4O]Cl (2ba). The compound was prepared by a procedure similar to that for 2aa. A mixture of 2-chloro-N(pyridin-2-ylmethyl)acetamide (0.54 g, 2.90 mmol) and 1-benzyl-2methyl-1H-imidazole (0.66 g, 3.50 mmol) was used. A yellow solid was obtained. Yield: 0.16 g (50%). 1H NMR (CDCl3): δ 3.22 (s, 3H, CH3), 4.55 (d, 2H, 2J(HH) = 6.0 Hz, CH2), 5.35 (s, 2H, CH2), 5.47 (s, 2H, CH2), 7.09−7.16 (m, 2H, Ar H), 7.20−7.25 (m, 2H, Ar H), 7.35− 7.42 (m, 4H, Ar H), 7.62 (td, 1H, 3J(HH) = 3.0, 9.0 Hz, Ar H), 7.73 G


Article


Organometallics Synthesis of C18H16ClFN4OPd (3c). The compound was prepared by a procedure similar to that for 3a. A mixture of PdCl2 (0.046 g, 0.26 mmol), 2ac (0.094 g, 0.26 mmol), and K2CO3 (0.144 g, 1.04 mmol) was used. A yellow solid was obtained. Yield: 0.082 g (68%). Mp: 155.3−155.8 °C. Anal. Calcd for C18H16ClFN4OPd: C, 46.47; H, 3.46; N, 12.04. Found: C, 46.89; H, 3.27; N, 11.58%. 1H NMR (CDCl3): δ 4.72 (s, 2H, CH2), 5.06 (s, 2H, CH2), 5.10 (s, 2H, CH2), 7.08−7.14 (m, 4H, Ar H), 7.21−7.39 (m, 3H, Ar H), 7.77 (t, 1H, 3J(HH) = 6.0 Hz, Py H), 7.83 (s, 1H, Ar H), 8.96 (d, 1H, 3J(HH) = 3.0 Hz, Py H). 13 C{1H} NMR (CDCl3): δ 53.6 (CH2), 56.4 (CH2), 57.1 (CH2), 115.8 (d, 2J (CF) = 21.8 Hz, CH), 120.5 (CH), 121.2 (CH), 122.2 (CH), 122.4 (CH), 130.1 (d, 3J (CF) = 7.5 Hz, CH), 132.1 (quaternary C), 138.7 (CH), 147.9 (CH), 153.6 (Pd−C), 162.6 (d, 1J(CF) = 247.5 Hz, CF), 164.1 (quaternary C), 166.4 (CO). Synthesis of C18H17ClN4OPd (3a′). In a 20 mL Schlenk flask were dissolved Pd(OAc)2 (0.12 g, 0.53 mmol), 2aa (0.183 g, 0.53 mmol), and NaOAc (0.087 g, 1.06 mmol) in dry DMF (10 mL) under a nitrogen atmosphere. The solution was stirred at room temperature overnight. The residue was washed with water and extracted with DCM twice. The extract was dried over anhydrous MgSO4 and evaporated to dryness under vacuum to give a solid. Diethyl ether was added, and the yellow solid that formed was collected on a frit and dried under vacuum. Yield: 0.149 g (62%). Mp: 158.6−159.1 °C. Anal. Calcd for C18H17ClN4OPd: C, 48.34; H, 3.83; N, 12.52. Found: C, 48.73; H, 4.09; N, 12.98%. 1H NMR (d6-DMSO): δ 4.77 (s, 2H, CH2), 5.08 (s, 2H, CH2), 5.14 (s, 2H, CH2), 6.97−7.20 (m, 5H, Ar H), 7.32−7.42 (m, 2H, Ar H), 7.80 (td, 1H, 3J(HH) = 6.0, 9.0 Hz, Py H), 8.03 (s, 1H, imi H), 8.98 (d, 1H, 3J(HH) = 3.0 Hz, Py H). 13 C{1H} NMR (d6-DMSO): δ 51.4 (CH2), 54.8 (CH2), 58.1 (CH2), 121.7 (CH), 123.0 (CH), 124.0 (CH), 128.7 (CH), 128.9 (CH), 129.1 (CH), 129.3 (CH), 132.9 (Pd−C), 134.1 (CH), 136.1 (quaternary C), 139.1 (CH), 147.3 (CH), 163.8 (quaternary C), 165.4 (CO). Synthesis of C19H19ClN4O2Pd (3b′). The compound was prepared by a procedure similar to that for 3a′. A mixture of Pd(OAc)2 (0.079 g, 0.35 mmol), 1b (0.132 g, 0.35 mmol), and NaOAc (0.058 g, 0.70 mmol) was used. A yellow solid was obtained. Yield: 0.074 g (44%). Mp: 151.3−151.6 °C. Anal. Calcd for C19H19ClN4O2Pd: C, 47.81; H, 4.01; N, 11.73. Found: C, 47.99; H, 4.33; N, 11.28%. 1H NMR (CDCl3): δ 3.79 (s, 3H, CH3), 4.71 (s, 2H, CH2), 5.05 (s, 2H, CH2), 5.07 (s, 2H, CH2), 6.76−6.93 (m, 3H, Ar H), 7.20−7.38 (m, 4H, Ar H), 7.77 (td, 1H, 3J(HH) = 9.0, 6.0 Hz, Py H), 7.84 (s, 1H, imi H), 8.96 (d, 1H, 3J(HH) = 3.0 Hz, Py H). 13 C{1H} NMR (d6-DMSO): δ 51.3 (CH2), 54.8 (CH2), 55.6 (CH3), 58.1 (CH2), 114.1 (CH), 114.7 (CH), 120.8 (CH), 121.7 (CH), 123.0 (CH), 124.0 (CH), 130.5 (CH), 132.8 (Pd−C), 134.1 (CH), 137.5 (CH), 139.2 (quaternary C), 147.3 (CH), 159.9 (quaternary C), 163.8 (quaternary C), 165.4 (CO). Synthesis of C18H16ClFN4OPd (3c′). The compound was prepared by a procedure similar to that for 3a′. A mixture of Pd(OAc)2 (0.079 g, 0.35 mmol), 1ac (0.128 g, 0.35 mmol), and NaOAc (0.056 g, 0.71 mmol) was used. A yellow solid was obtained. Yield: 0.062 g (38%). Mp: 168.2−168.8 °C. Anal. Calcd for C18H16ClFN4OPd: C, 46.47; H, 3.46; N, 12.04. Found: C, 46.79; H, 3.55; N, 11.65%. 1H NMR (CDCl3): δ 4.77 (s, 2H, CH2), 5.08 (s, 2H, CH2), 5.14 (s, 2H, CH2), 6.97−7.12 (m, 5H, Ar H), 7.32−7.42 (m, 2H, Ar H), 7.81 (td, 1H, 3J(HH) = 3.0, 9.0 Hz, Py H), 8.03 (s, 1H, imi H), 8.98 (d, 1H, 3JH,H = 6.0 Hz, Py H). 13C{1H} NMR (CDCl3): δ 52.1 (CH2), 55.4 (CH2), 58.3 (CH2), 116.6 (d, 2J (CF) = 21.8 Hz, CH), 120.5 (CH), 122.3 (CH), 124.9 (CH), 128.6 (quaternary C), 130.3 (d, 3J (CF) = 8.3 Hz, CH), 130.6 (CH), 135.3 (Pd−C), 138.2 (CH), 148.1 (CH), 163.2 (d, 1J(CF) = 249.0 Hz, CF), 163.4 (quaternary C), 164.9 (CO). Synthesis of C19H19ClN4OPd (4a). In a 20 mL Schlenk flask were dissolved PdCl2 (0.040 g, 0.23 mmol), 1ba (0.082 g, 0.23 mmol), and K2CO3 (0.127 g, 0.92 mmol) in dry DMF (10 mL) under nitrogen. The solution was heated at 50 °C overnight. After cooling, the solvent was removed completely under vacuum. The residue was washed with water and extracted with DCM twice. The extract was dried over anhydrous MgSO4 and evaporated to dryness under vacuum to give a solid. Diethyl ether was added, and the white solid that formed was

collected on a frit and dried under vacuum. Yield: 0.038 g (36%). Mp: 268.4−270.3 °C. Anal. Calcd for C19H19ClN4OPd: C, 49.47; H, 4.15; N, 12.14. Found: C, 49.95; H, 4.22; N, 11.74%. 1H NMR (CDCl3): δ 2.41 (s, 3H, CH3), 4.65 (s, 2H, CH2), 5.08 (s, 4H, CH2), 7.10−7.25 (m, 4H, Ar H), 7.34−7.38 (m, 4H, Ar H), 7.75 (td, 1H, 3J(HH) = 3.0, 9.0 Hz, Py H), 8.99 (d, 1H, 3J(HH) = 3.0 Hz, Py H). 13C{1H} NMR (d6-DMSO): δ 10.4 (CH3), 50.1 (CH2), 53.7 (CH2), 58.5 (CH2), 121.6 (CH), 123.1 (CH), 128.0 (CH), 128.5 (CH), 129.3 (CH), 130.2 (CH), 136.0 (Pd−C), 139.1 (quaternary C), 141.5 (quaternary C), 147.3 (CH), 163.8 (quaternary C), 165.3 (CO). Synthesis of C20H21ClN4O2Pd (4b). The compound was prepared by a procedure similar to that for 4a. A mixture of PdCl2 (0.056 g, 0.31 mmol), 2bb (0.118 g, 0.31 mmol), and K2CO3 (0.175 g, 1.26 mmol) was used. A white solid was obtained. Yield: 0.047 g (30%). Mp: 297.1−297.7 °C. Anal. Calcd for C20H21ClN4O2Pd: C, 48.89; H, 4.30; N, 11.40. Found: C, 48.90; H, 3.94; N, 10.94%. 1H NMR (CDCl3): δ 2.41 (s, 3H, CH3), 3.78 (s, 3H, COCH3), 4.65 (s, 2H, CH2), 5.04 (s, 2H, CH2), 5.09 (s, 2H, CH2), 6.64−6.87 (m, 3H, Ar H), 7.17−7.27 (m, 2H, Ar H), 7.30−7.38 (m, 2H, Ar H), 7.76 (td, 1H, 3J(HH) = 3.0, 9.0 Hz, Py H), 8.99 (d, 1H, 3J(HH) = 3.0 Hz, Py H). 13C{1H} NMR (d6-DMSO): δ 10.4 (CH3), 50.1 (CH2), 53.7 (CH2), 55.5 (OCH3), 58.5 (CH2), 113.6 (CH), 114.1 (CH), 120.0 (CH), 121.6 (CH), 123.0 (CH), 123.1 (CH), 130.1 (Pd−C), 130.5 (CH), 137.5 (CH), 139.1 (quaternary C), 141.5 (quaternary C), 147.3 (CH), 159.9 (quaternary C), 163.7 (quaternary C), 165.3 (CO). Synthesis of C19H18ClFN4OPd (4c). The compound was prepared by a procedure similar to that for 4a. A mixture of PdCl2 (0.040 g, 0.23 mmol), 2bc (0.086 g, 0.23 mmol), and K2CO3 (0.127 g, 0.92 mmol) was used. A white solid was formed. Yield: 0.051 g (51%). Mp: 262.9− 263.3 °C. Anal. Calcd for C19H18ClFN4OPd: C, 47.61; H, 3.78; N, 11.67. Found: C, 48.04; H, 4.15; N, 11.47%. 1H NMR (CDCl3): δ 2.43 (s, 3H, CH3), 4.65 (s, 2H, CH2), 5.06 (s, 2H, CH2), 5.08 (s, 2H, CH2), 7.03−7.14 (m, 5H, Ar H), 7.28−7.38 (m, 2H, Ar H), 7.77 (t, 1H, 3J(HH) = 9.0 Hz, Py H), 8.98 (d, 1H, J = 6.0 Hz, Py H). 13C{1H} NMR (d6-DMSO): δ 10.4 (CH3), 49.4 (CH2), 53.7 (CH2), 58.5 (CH2), 116.1 (d, 2J (CF) = 20.3 Hz, Ar C), 121.6 (CH), 122.9 (CH), 123.0 (CH), 130.4 (d, 3J (CF) = 9.0 Hz, overlap with Pd−C, Ar C), 132.3 (quaternary C), 139.1 (quaternary C), 141.5 (quaternary C), 147.3 (CH), 162.2 (d, 1J(CF) = 245.2 Hz, CF), 163.7 (quaternary C), 165.3 (CO). Single-Crystal X-ray Diffraction. Samples were collected at 150(2) K on a Bruker APEX II instrument equipped with a CCD area detector and a graphite monochromator utilizing Mo Kα radiation (λ = 0.71073 Å). The unit cell parameters were obtained by least-squares refinement. Data collection and reduction were performed using the Bruker APEX2 and SAINT software.24 Absorption corrections were performed using the SADABS program.25 All structures were solved by direct methods and refined by full-matrix least-squares methods against F2 with the SHELXTL software package.26 All non-H atoms were refined anisotropically. All H atoms were fixed at calculated positions and refined with the use of a riding model. Electron density attributed to heavily disordered solvent in 3a′ was removed from the structure (and the corresponding Fo values) with the SQUEEZE procedure implemented in PLATON.27 CCDC files 1402713 (3a), 1402578 (3a′), and 1402579 (4b) contain supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam. ac.uk/data_request/cif. Computational Studies. The computations were performed using the Gaussian 09 suite of programs.28 The geometries of 3a and 3a′ were optimized using the B3LYP and M06 density functionals with the 6-311+G(d,p) basis set. The structures were verified to be genuine minima on the potential energy surface with the harmonic vibrational frequencies. Validation of the computational method was obtained by comparing the results with available experimental values. Culture of Cell Lines. The tumor cells TOV21G, SW620, and NCI-H1688 were maintained in DMEM medium supplemented with 10% fetal bovine serum (FBS), penicillin (100 U/mL), and streptomycin (100 U/mL) under a humidified atmosphere consisting of 95% air and 5% CO2 at 37 °C. H


Article

Organometallics Cell Proliferation Assay. The 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) assay was carried out to assess the cytotoxicity of each compound. In a 96-well plate, 1 × 103 cells were plated in each well containing complete growth medium for 24 h. The cells were then incubated with each compound for 48 h. At the end of incubation, MTT (5 mg/mL) in PBS buffer was added to the media and incubated for 4 h at 37 °C. After removal of MTT solution, 150 μL of DMSO was added to each well to dissolve the formazan crystals, and the absorbance was determined at 550 nm with a plate reader (μQuant, BioTek Instruments, Inc., Winooski, VT, USA).

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ASSOCIATED CONTENT

* Supporting Information


S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.5b00586. NMR spectra for all products and crystallographic data of 3a, 3a′, and 4b (PDF) Crystallographic data of 3a, 3a′, and 4b (CIF) All computed molecule Cartesian coordinates (XYZ)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail for N.M.W.: [email protected]. *E-mail for H.M.L.: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the Ministry of Science and Technology of Taiwan for financial support of this work. We also thank the National Center for High-performance Computing of Taiwan for computing time and financial support of the Conquest software.

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