Synthesis of a palladium complex with a β-d -glucopyranosyl-thiosemicarbazone and its application in the Suzuki–Miyaura coupling of aryl bromides with phenylboronic acid

Inorganica Chimica Acta 435 (2015) 142–146

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Synthesis of a palladium complex with a b-D-glucopyranosylthiosemicarbazone and its application in the Suzuki–Miyaura coupling of aryl bromides with phenylboronic acid Alia-Cristina Tenchiu a, Iro-Konstantina Ventouri a, Georgia Ntasi a, Dimitrios Palles b, George Kokotos c, Dimitra Kovala-Demertzi d, Ioannis D. Kostas a,⇑ a

National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Vas. Constantinou 48, 11635 Athens, Greece National Hellenic Research Foundation, Theoretical & Physical Chemistry Institute, Vas. Constantinou 48, 11635 Athens, Greece c Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, 15771 Athens, Greece d Sector of Inorganic and Analytical Chemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece b

a r t i c l e

i n f o

Article history: Received 31 March 2015 Received in revised form 24 June 2015 Accepted 25 June 2015 Available online 2 July 2015 Keywords: Carbohydrate Thiosemicarbazone Glucopyranosyl-thiosemicarbazone Phosphane-free ligand Suzuki–Miyaura cross-coupling Catalysis

a b s t r a c t A palladium(II) complex with a known phosphane-free b-D-glucopyranosyl-thiosemicarbazone ligand has been prepared and characterized by spectroscopic studies. The ligand is bonded to the metal in a bidentate coordination mode via the azomethine nitrogen and the thiolate sulfur in the dimeric form. The application of this complex on the Suzuki–Miyaura coupling of aryl bromides with phenylboronic acid in DMF/K2CO3 at 100 °C for 24 h in air, using 0.1 mol% of palladium, afforded the corresponding biaryls in 54–91% yield. Crabtree’s test provided evidence that the real catalyst is mainly heterogeneous rather than homogeneous. Ó 2015 Elsevier B.V. All rights reserved.

1. Introduction Suzuki–Miyaura cross-coupling remains a powerful tool of organic synthesis for C–C bond formation with various industrial applications [1]. Since catalysis under phosphane-free conditions represents a challenge of high importance, in our efforts to develop new phosphane-free ligands for transition metal homogeneous catalysis, our attention has been focused on salicylaldehyde thiosemicarbazones [2–4], chalcogen-containing substituted Schiff-bases [5] and porphyrins [6,7]. Thiosemicarbazones are multidentate ligands and usually bonded to a transition metal leaving some potential donor sites unused. It has been found for hybrid ligands, that an additional coordination site as a stabilizing group during the course of the catalytic cycle could improve the catalytic efficiency of the complex despite no interaction with the metal is observed in the complex [8–10]. Thiosemicarbazones are known compounds for over one century and together with their metal complexes, they have been recognized as an important class of biochemical molecules possessing a wide range of biological activity, ⇑ Corresponding author. Tel.: +30 210 7273878; fax: +30 210 7273831. E-mail address: [email protected] (I.D. Kostas). http://dx.doi.org/10.1016/j.ica.2015.06.019 0020-1693/Ó 2015 Elsevier B.V. All rights reserved.

and are very promising in the treatment of several diseases [11–19]. However, the first few reports on their catalytic activities appeared in 90’s [20–23]. In the years 2004 and 2005, we (Kostas and Kovala-Demertzi) reported the first studies concerning the evaluation of thiosemicarbazones as ligands in palladiumcatalyzed Heck and Suzuki–Miyaura reactions, respectively, providing promising results even when the reactions were performed under aerobic conditions [2,3]. Since then, several other research teams started to study the catalytic activity of metal complexes with thiosemicarbazones towards C–C [24–38] as well as C–N [27,33,34,39,40] bond formation. One of our first palladium complexes with a thiosemicarbazone ligand, namely salicylaldehyde thiosemicarbazone palladium(II) chloride [3], as an efficient catalyst for the Suzuki–Miyaura coupling, is currently commercially available by numerous companies, such as Sigma–Aldrich. Recent studies by Singh in coupling reactions using Pd(II) complexes of organochalcogen ligands, particularly sulfur analogues, showed that in some cases the real catalyst is a soluble Pd(0) or other Pd(0)-particles [30,38]. We have previously reported a systematic study for the synthesis and characterization of a novel class of aromatic aldehyde/ketone 4-(b-D-glucopyranosyl)thiosemicarbazones [41],

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which were found to be inhibitors of glycogen phosphorylase [42], a target for the design of drugs against diabetes type 2. Since the evaluation of carbohydrate-derived thiosemicarbazones in palladium-catalyzed Suzuki–Miyaura coupling is limited to a complex in which a phosphane ligand is also coordinated to the metal [31], herein we report the synthesis of a palladium complex with one of the above-mentioned glucopyranosyl-thiosemicarbazones and its application in the Suzuki–Miyaura reaction. Its catalytic activity is also compared with that of salicylaldehyde thiosemicarbazones. 2. Experimental 2.1. General Ligand 1 was synthesized as previously described by us [41]. All other chemicals were commercially available. IR and FAR-IR spectra were recorded on a Bruker Tensor 27 or a Bruker Vertex 80v vacuum Fourier-Transform InfraRed (FT-IR) spectrometer. The NMR measurements were made using a Varian 300 or 600. Gas chromatography was undertaken using a Varian Star 3400 CX with a 30 m  0.53 mm DB5 column. Electron impact gas chromatography–mass spectrometry was carried out using a Varian Saturn 2000 with a 30 m  0.25 mm DB5-MS column. HRMS was determined by using a Thermo Scientific LTQ Orbitrap Velos (ESI) spectrometer; experimental details: (i) for the negative ESI-MS in DMF/MeOH (1:5): source voltage 4 kV, source temperature 50 °C, sheath gas flow rate 15, aux gas flow rate 5, capillary temperature 275 °C; (ii) for the positive ESI-MS in DMSO/MeOH (1:100): source voltage 4 kV, source temperature 50 °C, sheath gas flow rate 8, aux gas flow rate 0, capillary temperature 275 °C; (iii) for the positive ESI-MS in DMF/MeOH (1:5): source voltage 3 kV, source temperature 50 °C, sheath gas flow rate 15, aux gas flow rate 5, capillary temperature 280 °C. Elemental analysis for complex 2 was carried out on an Elementar Vario Micro elemental analyzer.

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(131 mg, 78%) as an orange solid, m.p. >260 °C. IR (KBr pellet): m 3317 (br), 2960, 1597, 1527, 1268, 1073, 1027, 876, 828, 674, 610 cm1. FAR-IR (PE film): m 506 (Pd–N), 331 (Pd–S), 283 (Pd–Cl) cm1. 1H NMR (600 MHz, DMSO-d6) (M/2): d 8.22–8.20 (m, 2H) and 8.06 (m, 2H) (N(4)H, CH@N, Harom), 7.48 (d, 3 J = 8.4 Hz, 2H, Harom), 5.04 (d, 3J = 3.5 Hz, 1H), 4.97 (d, 3J = 4.8 Hz, 1H), 4.92 (br s, 1H) and 4.61 (br s, 2H) ((4  OH exchangeable with D2O, 1-H), 3.68–3.65 (m, 1H), 3.53 (m, 1H) and 3.20–3.13 (m, 4H) (2-H, 3-H, 4-H, 5-H, 6-H, 60 -H), 1.29 (s, 9H, CH3(tBu)). 13C NMR (75.47 MHz, DMSO-d6): d 171.40 (C@S), 156.04 (Carom–tBu), 155.13 (CH@N), 133.39, 128.68, 126.12 and 126.09 (Carom), 86.54 (1-C), 78.72, 77.80, 72.57 and 70.00 (2-C, 3-C, 4-C, 5-C), 60.93 (6-C), 35.38 (CMe3), 31.32 (CH3(tBu)). HRMS (negative ESI-MS): calcd. for C18H26Cl2N3O5PdS [M/2+Cl] 572.0005, found 572.0001. HRMS (positive ESI-MS): calcd. for C36H52Cl2N6O10Pd2S2Na [M+Na]+ 1097.0525, found 1097.0537. Anal. Calc. for C36H52Cl2N6O10Pd2S24H2O (1148.77): C, 37.64; H, 5.26; N, 7.32%. Found: C, 37.71; H, 4.96; N, 7.32%. 2.4. General experimental procedure for the Suzuki–Miyaura coupling Aryl bromide (1.0 mmol), phenylboronic acid (183 mg, 1.5 mmol), K2CO3 (276 mg, 2.0 mmol), complex 2 in DMF (0.25 mM, 2 mL, 0.5 lmol) and dodecane (70 lL, 0.3 mmol) as internal standard were stirred at 100 °C in air for 24 h, and then allowed to cool to room temperature. After addition of water (5 mL) and extraction with dichloromethane (2  10 mL), the organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, passed through Celite and analyzed by GC and GC–MS. After evaporation of the volatiles, isolation of the pure biaryl was achieved by column chromatography on silica gel using hexane/AcOEt as eluent. All biaryls are known compounds and were characterized by 1H NMR spectra. 3. Results and discussion

2.2. NMR data for ligand 1 3.1. Synthesis and characterization of the palladium complex Although NMR spectra of ligand 1 in CDCl3 have previously been reported by us [41], for comparison purposes with the metal complex, we give here the NMR data in DMSO-d6. 1H NMR (300.13 MHz): d 11.92 (s, 1 H, N(2)H), 8.71 (d, 3J1-H,N(4)H = 9.0 Hz, 1H, N(4)H), 8.07 (s, 1H, CH@N), 7.76 (d, 3J = 9.0 Hz, 2H, Harom), 7.45 (d, 3J = 8.1 Hz, 2H, Harom), 5.94 (dd, 3J1-H,2-H = 9.0 Hz, 1H, 1-H), 5.46–5.29 (m, 2H) and 5.01–4.94 (m, 1H) (2-H, 3-H, 4-H), 4.25–4.21 (m, 1H), 4.07–4.01 (m, 1H) and 3.97–3.32 (m, 1H) (5-H, 6-H, 60 -H), 2.00, 2.00, 1.97 and 1.93 (4  s, 12H, CH3CO), 1.30 (s, 9H, CH3(tBu)); 13C NMR (75.47 MHz): d 178.18 (C@S), 170.04, 169.59, 169.57 and 169.38 (C@O), 153.21 (Carom–tBu), 143.77 (CH@N), 131.06, 127.46 and 125.52 (Carom), 81.41 (1-C), 72.68 (3-C), 72.23 (2-C), 70.08 (5-C), 67.98 (4-C), 61.79 (6-C), 34.64 (CMe3), 30.94 (CH3(tBu)), 20.58, 20.43, 20.39 and 20.35 (CH3CO). 2.3. Chloro[4-tert-butyl-benzaldehyde 4-(b-Dglucopyranosyl)thiosemicarbazone]palladium(II) dimer (2) Ligand 1 (177 mg, 0.31 mmol) was added under argon to a mixture of K2PdCl4 (101 mg, 0.31 mmol) in dry methanol (5 mL) at room temperature and stirred at this temperature for 5 days. The dark red mixture of K2PdCl4 turned to orange and a precipitate was formed, which was filtered off, washed thoroughly with water, methanol, ether and dried in the dessicator. This solid was then dissolved in a minimum amount of DMF/MeOH (1:1), ether was added and left at room temperature overnight forming a precipitate that filtered out and dried in the dessicator, yielding 2

Synthesis of Pd(II)/glucopyranosyl-thiosemicarbazone 2 is outlined in Scheme 1. Treatment of 4-tert-butyl-benzaldehyde 4-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)thiosemicarbazone (1) with K2PdCl4 (1 equiv.) in MeOH, afforded in one-pot process, both de-acetylation of the glucose moiety and also formation of a metal complex as an orange solid. Unfortunately, attempts to obtain crystals of the complex suitable for X-ray crystal structure determination were unsuccessful. The coordination mode in 2 was determined by spectroscopic techniques, suggesting that the ligand is bonded to palladium in an N,S-bidentate coordination mode via the azomethine nitrogen N(1) and the sulfur atom, forming a five-membered chelate ring. The disappearance of the acetyl group resonances in the 1H and 13 C NMR spectra of 2 compared to ligand 1 as well as the absence in the FT-IR spectrum of 2 of the characteristic band at 1749 cm1 due to C@O stretching vibration in 1, clearly indicate the presence of free hydroxyl groups in the glucose moiety of 2. This is also confirmed by the OH signals in the 1H NMR spectrum of the complex (exchangeable with D2O) and a broad signal in its IR spectrum at 3317 cm1. Palladation of the ortho-carbon at the aryl ring must be ruled out because on one hand, six protons are assigned in the region 7.48–8.22 ppm (four aromatic protons and the two protons N(4)H and CH@N) in the 1H NMR spectrum of 2 (M/2), and on the other hand, a strong deshielding of the carbon nucleus in the 13 C NMR upon palladation of the ortho-carbon [16] was not observed. Thiosemicarbazones are known to exhibit thione-thiol tautomerism in solution, and depending on the conditions, they

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OH 4 65

HO HO OAc O

AcO AcO

H N

OAc

H N

3

K2PdCl4 N

S

t

1

Bu

MeOH 78%

t

Bu

O 2

H (3) (2)(1) N N N (4) OH 1 S Pd Cl Cl Pd N

2

N

t

S

Bu

HO N H

OH OH

O

OH

Scheme 1. Synthesis of the palladium complex and atom numbering used for the NMR spectra.

are coordinated to a metal ion via the azomethine nitrogen and the sulfur atom either as a neutral thione or a thiolate anion [14,16,17,19,28,29,35,36]. The singlet of N(2)H at 11.92 ppm in the 1H NMR spectrum of the ligand vanish in the complex due to deprotonation, suggesting enolization and coordination of the thiolate sulfur to the Pd(II) ion [29,35,39,40]. In the 13C NMR spectrum of the ligand, the C@N and C@S signals appear at 143.77 and 178.18 ppm, respectively. Upon coordination, a downfield shift is observed for the C@N signal (11 ppm) and also an upfield shift for the C–S signal (7 ppm) compared to the thione carbon of the free ligand. These observations are consistent with the N,S-coordination and thioenolization of the C@S of the thiosemicarbazone moiety [16,29,39,40]. Although, assignment of each individual band to a specific vibration has not been attempted for the infrared spectrum of the palladium complex 2, it shows differences compared to that of ligand 1 in the 600–1600 cm1 region, which are attributable to the coordinated thiosemicarbazone moiety. The bands at 506, 331 and 283 cm1 in the FAR-IR spectrum of 2 also support coordination of palladium with the azomethine nitrogen, the thiolate sulfur and the chlorine atom, respectively [3,28]. A peak in the negative ESI-MS of 2 corresponded exactly to the formula [M/2+Cl]. In its positive ESI-MS using DMSO/MeOH for the injection of the sample, we observed a band corresponding exactly to the formula of the dimeric structure [M+Na]+, while in the positive ESI-MS using DMF/MeOH as solvent, a peak was in accordance to the formula [M+MeOH]+. 3.2. Suzuki–Miyaura cross-coupling Complex 2 is insoluble in most organic solvents, but it is soluble in dimethylformamide, and thus, the study of its catalytic activity towards the Suzuki–Miyaura reaction of several electron-rich and electron-poor aryl bromides with phenylboronic acid was performed in this solvent using K2CO3 as a base. Catalysis was performed in air at relatively low palladium loading (0.1 mol%) at 100 °C for 24 h (Scheme 2, Table 1). Under these conditions, conversions and isolated yields for the cross-coupling products were 60–99% and 54–91%, respectively. A sterically demanding orthosubstituted aryl bromide displayed a slightly lower yield compared

OH HO HO

O OH

ArX + PhB(OH) 2

H N

N N S Pd Cl

2 Pd (0.1 mol%) DMF/K2CO3 100 °C, 24 h, air

Scheme 2. Suzuki–Miyaura coupling.

tBu

ArPh

to the bromide with the same substituent at para-position (compare entries 2 and 3). A reaction time of 4 h for the coupling of 4-bromobenzonitrile afforded the corresponding biaryl with 28% conversion (entry 13). It is also mentioned that under the same conditions (100 °C, 24 h, air) using 0.1 mol% of Pd, the conversions for cross-coupling products were higher compared to those observed for salicylaldehyde thiosemicarbazones previously reported by us [3], e.g. 69% versus 53% for 4-bromo-anisole, 99% versus 88% for 4-bromobenzonitrile, 98% versus 83% for 1-bromo-4-nitrobenzene. Unfortunately, in the present work a significant amount of unsubstituted biphenyl as homo-coupling by-product was observed for the deactivated bromides in contrast to the activated analogues. Complex 2 was also applied to the cross-coupling of phenylboronic acid with 4-chloro-anisole or 1-chloro-4-nitrobenzene under the above-mentioned conditions, leading to the corresponding biaryls with conversions of only 4% and 12%, respectively, indicating that the catalyst is not applicable for aryl chlorides (entries 15–16) in contrast to another carbohydrate-derived thiosemicarbazone, in which however, PPh3 is also bonded to palladium [31]. It is also pointed out that a salicylaldehyde thiosemicarbazone displayed a higher conversion for 1-chloro-4-nitrobenzene compared to complex 2 [3]. Since Hg(0) is known to poison heterogeneous catalysis and has little or no effect on homogeneous catalysts [43–45], Suzuki– Miyaura reaction for the 4-bromo-anisole was also performed in the presence of a high excess of Hg(0) (ca. 350 equiv. versus Pd) throughout the experiment at 100 °C for 24 h (entry 4). The conversion towards the cross-coupling product was dramatically decreased from 69% to 8%, and a significant amount of homocoupling by-product was observed (compare entries 3 and 4). This is probably an indication for a heterogeneous catalysis, but the experiment is not definitive by itself and becomes ambiguous in the case that mercury reacts with the pre-catalyst, and thus control experiments are required. In such a control experiment, complex 2 in DMF was stirred with Hg(0) at r.t. for 2 h, and then the solution was separated from mercury and transferred with a syringe to another flask for the catalytic reaction (entry 5), yielding the coupling product with 40% conversion. In another control experiment in which Hg(0) was stirred with complex 2 at 100 °C instead of r.t. before removal of mercury, the conversion towards the product was only 8% (entry 6). These experiments show that complex 2 reacts with Hg(0) at least at elevated temperature, and thus Hg test is not efficient by itself to distinguish the nature of catalysis. Since dibenzo[a,e]cyclooctatetraene (DCT) is known to poison homogeneous catalysts, but not heterogeneous ones (e.g. Pd catalysts), we performed the so-called Crabtree’s test [44,46]. A solution of DCT (1.3 equiv. versus Pd) and complex 2 in DMF was stirred at r.t. for 3 h, and then the Suzuki–Miyaura coupling was performed in the presence of DCT at 100 °C for 24 h, yielding the coupling product with a conversion closed to that observed in the absence of DCT (compare entries 3 and 7). This observation as well as the appearance of the gray color of palladium black during the course

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A.-C. Tenchiu et al. / Inorganica Chimica Acta 435 (2015) 142–146 Table 1 Suzuki–Miyaura coupling of aryl halides with phenylboronic acid.a Entry 1

ArX

Coupling product

Me

2

Br

Conversion (%)b ArPhc (PhPh)d

Yield (%)e

68 (13)

59

60 (5)

54

69 (10) 8 (22) 40 (9) 8 (6) 60 (10) 95 (5)

60

96

88

96 (4)

89

98 (2)

91

99 (1) 28 (1) 98 (2)

90

4 (27)

g

12 (4)

g

Me

OMe

OMe

Br

3 4 5 6 7 8

(Hg test)f (Hg control; r.t.)h (Hg control; 100 °C)i (Crabtree’s test) j

MeO

MeO

Br

9 10

Br

Br PhC O

Br

PhC O

O2 N

Br

O2 N

11 12 13k 14

NC

Br

NC

OHC

Br

OHC

MeO

Cl

MeO

O2 N

Cl

O2 N

15 16

a b c d e f g h i j k

g g g g

86

g

90

Reaction conditions: ArX (1.0 mmol), PhB(OH)2 (1.5 mmol), K2CO3 (2.0 mmol), dodecane (0.3 mmol), 0.25 mM solution of 2 in DMF (2 mL, 0.5 lmol), 100 °C, 24 h, air. Determined by GC using dodecane as internal standard. Cross-coupling product ArPh. Homo-coupling by-product. Isolated yield for ArPh after column chromatography. Addition of 1 drop of Hg (ca. 70 mg, ca. 350 lmol). Hg was present in the reaction solution throughout the experiment. Not determined. Complex 2 in DMF was stirred with Hg (ca. 70 mg) at r.t. for 2 h, and Hg was then removed from the reaction solution. Complex 2 in DMF was stirred with Hg (ca. 70 mg) at 100 °C for 2 h, and Hg was then removed from the reaction solution. DCT (0.26 mg, 1.3 lmol) was stirred with complex 2 in DMF at r.t. for 3 h, and then catalysis was performed in the presence of DCT. Reaction time: 4 h.

of some catalytic reactions – in particular with electron-rich bromides – suggest that catalysis is mainly performed via a heterogeneous mode of action and that complex 2 is a pre-catalyst which serves a reservoir of Pd(0) species as the real catalyst. It is proposed that the molecular complex is decomposed under the reaction conditions to Pd(0) nanoparticles or some other Pd(0) species – the chemical nature of which was not clarified – which are responsible for the catalytic action, in accordance to a previous study for some Pd(II) complexes of organochalcogen ligands [38]. The Pd(0) species formed by the decomposition of complex 2 give rise to the conversion of aryl bromides compared to the analogous salicylaldehyde thiosemicarbazones, but they lack of selectivity as significant amounts of homo-coupling by-products were also observed, and in addition, they are less active for the more electronically deactivated aryl chlorides. In our previous investigations, the salicylaldehyde moiety stabilizes a mononuclear complex in a tridentate fashion [2,3], while in the present work the carbohydrate-derived binuclear complex seems to lack of sufficient stability under the reaction conditions.

4. Conclusions In summary, a known b-D-glucopyranosyl-thiosemicarbazone was used for the synthesis of a new chelate palladium complex as a dimer in a bidentate fashion via the azomethine nitrogen

and the thiolate sulfur. Its evaluation in the Suzuki–Miyaura reaction of various aryl bromides under aerobic conditions in relatively low palladium loading displayed good yields towards the formation of cross-coupling products, while it is not applicable for the coupling of aryl chlorides. Although the complex presented in this work displayed higher conversions of aryl bromides to cross-coupling products compared to a commercially available palladium complex with a salicylaldehyde thiosemicarbazone ligand, the introduction of the carbohydrate instead of the salicylaldehyde function on a thiosemicarbazone ligand should not be considered as advantageous due to terms of solubility of the complex, catalyst fragility and formation of homo-coupling by-products. There is evidence that this carbohydrate-derived binuclear complex is decomposed to Pd(0) particles under the reaction conditions, which act as the real catalyst. In accordance to literature information, the additional coordination of a phosphane ligand with the metal in carbohydrate-derived thiosemicarbazone complexes may lead to a real advantage, but however, this approach stands away from phosphane-free conditions. Therefore, our investigation provides information for the effects of the carbohydrate function on the stability and catalytic activity of thiosemicarbazones under aerobic and phosphane-free conditions, and it should be considered as a complementary study for the application of thiosemicarbazones in coupling reactions, underlying that carbohydrate-derived thiosemicarbazones are rarely described to be used for the Suzuki–Miyaura coupling.

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