Palladium Catalysts with Sulfonate-Functionalized-NHC Ligands for

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Organometallics 2011, 30, 684–688 DOI: 10.1021/om100960t

Palladium Catalysts with Sulfonate-Functionalized-NHC Ligands for Suzuki-Miyaura Cross-Coupling Reactions in Water Fernando Godoy,*,† Candela Segarra,‡ Macarena Poyatos,‡ and Eduardo Peris*,‡ †

Departamento de Quı´mica de los Materiales Facultad de Quı´mica y Biologı´a, Universidad de Santiago de Chile, Santiago, Chile, and ‡Departamento de Quı´mica Inorg anica y Org anica, Universitat Jaume I, Avenida Vicente Sos Baynat s/n, Castell on. E-12071, Spain Received October 4, 2010

Four new Pd(II) complexes containing sulfonate-functionalized N-heterocyclic carbene ligands have been synthesized. All new complexes are palladium bis-NHCs, in which the ligands adopt a monodentate, bis-chelating, and pincer coordination form, so that a good comparison between their catalytic activities can be performed. The complexes have been used in the Suzuki-Miyaura crosscoupling reaction between aryl halides and phenylboronic acid in water and in iPrOH/water. The bisNHC-palladium complex 1, in which the two NHC ligands are in a relative cis configuration, affords the best catalytic outcomes, with high TON values of 105 for 4-bromoacetophenone and 3.7
104 for 4-chloroacetophenone.

Introduction During the last two decades, there has been an increasing interest in the use of water as solvent for many homogeneously catalyzed reactions.1 Cost, environmental benefits, and safety are among the reasons most often argued to justify the replacement of organic solvents by water in organic transformations. The use of water in Pd-catalyzed crosscoupling reactions goes back to the early development of the Suzuki-Miyaura coupling,2 with the first example being reported by Calabrese and co-workers in 1990.3 Since then, a large number of water-soluble Pd catalysts bearing hydrophilic ligands have been reported, and several reviews have been devoted to this subject.4 Although the introduction of N-heterocyclic carbene ligands (NHCs) to the coordination sphere of metal complexes has a series of advantages, such as *To whom correspondence should be addressed. E-mail: fernando. [email protected] (F.G.); [email protected] (E.P.). (1) Lamblin, M.; Nassar-Hardy, L.; Hierso, J. C.; Fouquet, E.; Felpin, F. X. Adv. Synth. Catal. 2010, 352, 33. Lindstrom, U. M. Chem. Rev. 2002, 102, 2751. Herrmann, W. A.; Kohlpaintner, C. W. Angew. Chem., Int. Ed. Engl. 1993, 32, 1524. Shaughnessy, K. H. Chem. Rev. 2009, 109, 643. (2) Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki, A. J. Am. Chem. Soc. 1985, 107, 972. (3) Casalnuovo, A. L.; Calabrese, J. C. J. Am. Chem. Soc. 1990, 112, 4324. (4) Carril, M.; SanMartin, R.; Dominguez, E. Chem. Soc. Rev. 2008, 37, 639. Shaughnessy, K. H. Eur. J. Org. Chem. 2006, 1827. Bai, L.; Wang, J. X. Curr. Org. Chem. 2005, 9, 535. Shaughnessy, K. H.; DeVasher, R. B. Curr. Org. Chem. 2005, 9, 585. Franzen, R.; Xu, Y. J. Can. J. Chem.-Rev. Can. Chim. 2005, 83, 266. Genet, J. P.; Savignac, M. J. Organomet. Chem. 1999, 576, 305. (5) Turkmen, H.; Can, R.; Cetinkaya, B. Dalton Trans. 2009, 7039. (6) Roy, S.; Plenio, H. Adv. Synth. Catal. 2010, 352, 1014. (7) Gu, S. J.; Xu, H.; Zhang, N.; Chen, W. Z. Chem.-Asian J. 2010, 5, 1677. (8) Mesnager, J.; Lammel, P.; Jeanneau, E.; Pinel, C. Appl. Catal. A: Gen. 2009, 368, 22. Ohta, H.; Fujiharaa, T.; Tsuji, Y. Dalton Trans. 2008, 379. Yang, C.-C.; lin, P.-S.; Liu, F.-C.; Lin, I. J. B. Organometallics 2010, 29, 5959. pubs.acs.org/Organometallics

Published on Web 02/03/2011

stability and tolerance to a variety of functional groups, the number of Pd(NHC) complexes for homogeneous catalysis in water is limited to a very few recent examples.5-9 Since the description of the first water-soluble palladium complex with a NHC ligand functionalized with a noncoordinating sulfonate,10 there has been a number of palladium complexes with similar substituents that have been applied for catalytic purposes.6,11 Among the wide range of palladium-catalyzed C-C coupling reactions, Suzuki-Miyaura coupling between an arylboronic acid and an aryl halide is one of the most widely used protocols for the synthesis of biphenyls due to the good tolerance of various functional groups, and for this reason, finding a way to perform such a transformation in an environmentally benign manner is a challenge for the researchers in homogeneous catalysis. However, only a few examples of this reaction performed in aqueous media have recently been reported.5-7,12 Among the complexes bearing chelating NHC ligands,13 pincer NHC-based metal complexes have appeared as an interesting type of catalysts that can provide improved catalytic properties.14 We initially obtained a series of pincerNHC-palladium complexes that showed very good activity in (9) Tu, T.; Feng, X. K.; Wang, Z. X.; Liu, X. Y. Dalton Trans. 2010, 39, 10598. (10) Moore, L. R.; Cooks, S. M.; Anderson, M. S.; Schanz, H. J.; Griffin, S. T.; Rogers, R. D.; Kirk, M. C.; Shaughnessy, K. H. Organometallics 2006, 25, 5151. (11) Fleckenstein, C.; Roy, S.; Leuthausser, S.; Plenio, H. Chem. Commun. 2007, 2870. (12) Han, Y.; Lee, L. J.; Huynh, H. V. Organometallics 2009, 28, 2778. Ines, B.; SanMartin, R.; Churruca, F.; Dominguez, E.; Urtiaga, M. K.; Arriortua, M. I. Organometallics 2008, 27, 2833. (13) Mata, J. A.; Poyatos, M.; Peris, E. Coord. Chem. Rev. 2007, 251, 841. Poyatos, M.; Mata, J. A.; Peris, E. Chem. Rev. 2009, 109, 3677. (14) Pugh, D.; Danopoulos, A. A. Coord. Chem. Rev. 2007, 251, 610. Peris, E.; Crabtree, R. H. C. R. Chim. 2003, 6, 33. Peris, E.; Crabtree, R. H. Coord. Chem. Rev. 2004, 248, 2239. r 2011 American Chemical Society

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Organometallics, Vol. 30, No. 4, 2011 Scheme 1

C-C coupling reactions including Heck, Suzuki-Miyaura, and Sonogashira.15 On the basis of these previous results, we now present our new studies on the preparation of a series of palladium complexes with NHC ligands containing sulfonate functionalities, which have been tested in the Suzuki-Miyaura coupling of a wide set of substrates in water. This study gives a good opportunity to compare the catalytic outcomes of monodentate and bis-chelating and pincer-NHC-based palladium complexes in aqueous solvents.

Results and Discussion We initially prepared a series of sulfonate-functionalizedNHC complexes of Pd(II), in which the ligands behave as monodentate and bis-chelating and pincer coordinated. We thought that the choice of this type of coordination modes should cover a wide set of topologies of palladium NHC complexes that have proved efficient catalytic properties in nonaqueous solvents. The preparation of the ligand precursors was based on the use of 1,3-propane sultone as alkylating agent, as previously used for the preparation of other sulfonate-functionalized-NHC ligands,10,16 such as N,N0 -(methyl)(propanesulfonate)imidazolium,17 1a (Scheme 1). As depicted in Scheme 2, the general preparation of complexes 1-3 implied the reaction between [Pd(OAc)2] and the corresponding imidazolium salt during 12 h between 80 and 160 °C in DMSO. All complexes were very soluble in H2O and partially soluble in the lighter alcohols such as MeOH and EtOH. The complexes were very insoluble in most organic solvents such as CH2Cl2, CHCl3, Et2O, THF, and acetone. All three complexes, 1-3, were characterized by means of NMR spectroscopy and high-resolution mass spectrometry (ESI-TOF-MS). Only compound 1 gave satisfactory elemental analysis because 2 and 3 were highly hygroscopic. Compound 1 shows 13CNMR signals that are diagnostic for Pd(NHC) complexes with mutually cis NHCs. The resonance due to the (15) Loch, J. A.; Albrecht, M.; Peris, E.; Mata, J.; Faller, J. W.; Crabtree, R. H. Organometallics 2002, 21, 700. Peris, E.; Loch, J. A.; Mata, J.; Crabtree, R. H. Chem. Commun. 2001, 201. (16) Virboul, M. A. N.; Lutz, M.; Siegler, M. A.; Spek, A. L.; van Koten, G.; Gebbink, R. Chem.;Eur. J. 2009, 15, 9981. (17) Azua, A.; Sanz, S.; Peris, E. Organometallics 2010, 29, 3661. (18) Huynh, H. V.; Ho, J. H. H.; Neo, T. C.; Koh, L. L. J. Organomet. Chem. 2005, 690, 3854. (19) Hahn, F. E.; Foth, M. J. Organomet. Chem. 1999, 585, 241. Herrmann, W. A.; Schwarz, J.; Gardiner, M. G. Organometallics 1999, 18, 4082. Herrmann, W. A.; Elison, M.; Fischer, J.; Kocher, C.; Artus, G. R. J. Chem.;Eur. J. 1996, 2, 772.

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Ccarbene is displayed at 163.9 ppm, in the typical region shown for cis-unbridged ylidenes of the type PdX2(NHC)218,19 (transNHCs appear at lower fields, ∼180 ppm).18 The NMR spectra of 2 and 3 are consistent with the 2-fold symmetry of the complexes. The most representative 13C NMR signals are those due to the carbene carbons, which appear at 169.3 (2) and 166.5 (3) ppm. Because the introduction of pyridine ligands has demonstrated to provide highly active catalysts for various Pdmediated C-C reactions, by the so-called PEPPSI effect (pyridine-enhanced precatalyst preparation, stabilization, and initiation),20 we also prepared the pyridine-substituted NCN-pincer complex 4, by reaction of 3 with pyridine in the presence of silver triflate. This complex was characterized by NMR spectroscopy and ESI-TOF-MS and gave satisfactory elemental analysis. Regarding the NMR data, its most representative 13C NMR signal is the one due to the metalated carbene carbon at 167.9 ppm. We have tested the Suzuki-Miyaura coupling between phenylboronic acid and aryl halides in water. We first carried out a catalyst screening by comparing the activity of 1-4 in the coupling of 4-bromoacetophenone and 4-chloroacetophenone with phenylboronic acid. The reactions were carried out in neat water at 110 °C with a 1 mol % of catalyst loading in the presence of K2CO3. The choice of the base was done according to previous studies made by Chen and coworkers, in which a complete analysis on the effect of the base for the same reaction was performed using their triazole-based-NHC palladium catalysts.7 We chose these two haloacetophenones as substrates for this initial reaction due to their high solubility in water. The activation of 4-chloroacetophenone required the addition of tetrabutylammonium bromide (TBABr) as phase transfer catalyst. The reactions were monitored by GC analysis after the appropriate intervals. The results are listed in Table 1. As can be seen from the data shown in Table 1, complexes 1, 3, and 4 are very active in the arylation of 4-bromoacetophenone (yields above 90%, entries 2, 6, and 8), while complex 2 provides only a moderate yield (59%, entry 4). When the more inert 4-chloroacetophenone is used, only compound 1 affords a high catalytic outcome (87%, entry 1), while 3 and 4 provide a moderate yield of the final product (entries 5 and 7). According to the activities shown for the coupling between 4-bromoacetophenone and phenylboronic acid, catalysts 1 and 3 were the most active ones. This observation implies that the presence of the pyridine ligand in 4 does not provide the expected catalytic enhancement compared to catalyst 3. To further analyze the catalytic activities of complexes 1 and 3, we studied the coupling reaction of 4-bromoacetophenone and 4-chloroacetophenone with different catalyst loadings ranging from 0.1 to 10-3 mol %. The results are listed in Table 2. As can be seen, both 1 and 3 show excellent activities in the coupling of 4-bromoacetophenone when catalyst loadings as low as 10-3 mol % are used, although 1 provides a higher activity, in terms of both yield and reaction time (compare entries 6 and 12). These data compare well with (20) Organ, M. G.; Abdel-Hadi, M.; Avola, S.; Hadei, N.; Nasielski, J.; O’Brien, C. J.; Valente, C. Chem.;Eur. J. 2007, 13, 150. Organ, M. G.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Valente, C. Chem.;Eur. J. 2006, 12, 4749. O’Brien, C. J.; Kantchev, E. A. B.; Chass, G. A.; Hadei, N.; Hopkinson, A. C.; Organ, M. G.; Setiadi, D. H.; Tang, T. H.; Fang, D. C. Tetrahedron 2005, 61, 9723.

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Godoy et al. Scheme 2

Table 1. Aqueous Suzuki-Miyaura Coupling Reaction of Aryl Halides and Phenylboronic Acid Using Complexes 1-4a

entry 1 2 3 4 5 6 7 8

catalyst 1 2 3 4

X Cl Br Cl Br Cl Br Cl Br

t (h) 12 4 12 4 12 4 12 4

Table 2. Aqueous Suzuki-Miyaura Reaction of Aryl Halides and Phenylboronic Acid Using Catalysts 1 and 3a

yield (%)b 87 >99 39 59 58 >99 51 90

a

Reactions conditions: aryl halide (1 mmol), phenylboronic acid (1.2 mmol), K2CO3 (1.5 mmol), and 1 mol % of catalyst in 5 mL of H2O at 110 °C. All reactions with 4-chloroacetophenone were performed with addition of TBABr (1.5 mmol). b Yields determined by GC using anisole as internal standard.

previously published results for the coupling of 4-bromoacetophenone.7 For the reactions carried out with 4-chloroacetophenone, 1 affords a good activity when catalyst loadings of 10-1 or even 10-2 mol % are used (entries 1 and 2), but its activity dramatically decreases at lower catalyst loadings. For the same substrate, 3 affords a moderate activity when a catalyst loading of 0.1 mol % is used (entry 7). The activity of 1 in the coupling of 4-chloroacetophenone compares well with the results recently published by C-etincaya and co-workers, although in their case a catalyst loading of 1 mol % was used.5 One of the most important problems in the use of neat water in the Suzuki-Miyaura coupling is the poor solubility of most coupling partners. In order to circumvent this problem, mixtures of alcohol and water are often used.6,11,21 In order to widen the number of aryl halide substrates that we could use in the coupling reaction, we decided to perform (21) Pschierer, J.; Peschek, N.; Plenio, H. Green Chem. 2010, 12, 636. Fleckenstein, C. A.; Plenio, H. Green Chem. 2007, 9, 1287.

entry

catalyst

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

1

3

catalyst loading (%) 10-1 10-2 10-3 10-1 10-2 10-3 10-1 10-2 10-3 10-1 10-2 10-3

X

t (h)

yield (%)b

TONc

Cl

12

Br

2

Cl

12

Br

3

85 76 37 >99 >99 >99 52 31 18 >99 >99 87

850 7600 37 000 1000 10 000 100 000 520 3100 18 000 1000 10 000 87 000

a Reaction conditions: aryl halide (1 mmol), phenylboronic acid (1.2 mmol), K2CO3 (1.5 mmol), and catalyst in 5 mL of H2O at 110 °C. All reactions with chloro halides were performed with addition of TBABr (1.5 mmol). b Yields determined by GC using anisole as internal standard. c TON = (mmol of product)/(mmol of catalyst).

the reaction in a 1:1 mixture of H2O/iPrOH, using catalysts 1 and 3. As can be seen from the data shown in Table 3, this mixture of solvents allows the effective coupling of a variety of bromoarenes, including nonactivated ones. For the coupling with chloroarenes, both 1 and 3 are very active in the coupling with 4-chloroacetophenone (entries 1 and 9), but only 1 is capable of effectively activating other chloroarenes such as chorobenzene (entry 3). These data are difficult to compare with the results provided by other authors using the same substrates and reaction conditions where conversions (generally based on reactants) instead of yields (based on products) are reported.6,11 In order to illustrate this point, we decided to study the time course of the reactions between phenylboronic acid and two chloroarenes (Figure 1). As can be seen from the three plots depicted in Figure 1, the coupling

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Table 3. Suzuki-Miyaura Reaction of Aryl Halides and Phenylboronic Acid in H2O/iPrOHa,b

entry

catalyst

X

R

t (h)

yield (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

1

Cl

COCH3 OCH3 H CH3 COCH3 OCH3 H CH3 COCH3 OCH3 H CH3 COCH3 OCH3 H CH3

12

>99 35 73 34 >99 86 99 94 84 12 31 12 >99 81 92 73

Br

3

Cl

Br

4

12

4

a

Reaction conditions: aryl halide (1 mmol), phenylboronic acid (1.2 mmol), K2CO3 (1.5 mmol), and 1 mol % of catalyst. Reactions performed in a mixture of 2.5 mL of H2O/2.5 mL of iPrOH at 110 °C. b All reactions with chloro halides were performed with addition of TBABr (1.5 mmol). c Yields determined by GC using anisole as internal standard.

reaction of 4-chloroacetophenone with phenylboronic acid affords almost quantitative yield of the final biphenyl product in just two hours. On the other hand, the maximum yield achieved for the coupling of 4-chlorotoluene is 35%, after 12 h. However, the conversion for this latter substrate is above 80%, as can be seen from the corresponding graphic, a result that is mainly due to the transformation of substrates in other products than the desired one. For this reaction, we also detected the formation of 1,10 -biphenyl as a consequence of the homocoupling of phenylboronic acid. We also detected some other minor unidentified products. These results are interesting because they suggest that the low catalytic activity of catalyst 1 when deactivated chloroarenes are used is not due to the deactivation of the catalyst along the reaction course, but to the formation of other kinetically favored products. These results suggest that probably a careful optimization of the reaction conditions may afford better outcomes. It is interesting to see that the activity shown by the complex containing the mono-NHC ligand, 1, shows a higher catalytic activity than complex 3. When the first NHC-based-pincerpalladium complexes were reported,15 one of their main achievements was precisely their capability to activate C-Cl bonds compared to other known Pd-NHC compounds, but this only happened at very high temperatures when high-temperatureboiling solvents were used such as DMSO or DMF. For homogenously catalyzed reactions in water we have a strong temperature limitation, so we believe that we may not be able to take advantage of the extraordinary high stability of pincer-type complexes 3 and 4, by using them in reactions carried out at high temperatures. In this regard, and in the course of the processing of the present article, Tu and co-workers described the catalytic activity of a hydrophilic pyridine-bridged bis-benzimidazolylidene palladium pincer complex that is extraordinarily active in the Suzuki-Miyaura coupling of a series of bromoarenes in aqueous solvents, although its activity has not been tested in the coupling of chloroarenes.9

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Conclusions In this work we have prepared a set of four new palladium complexes with NHC ligands incorporating sulfonate functionalities. The presence of the sulfonate makes these new palladium complexes water-soluble, and insoluble in most organic solvents. All four complexes have been tested in the Suzuki-Miyaura coupling of a series of bromo- and chloroarenes with phenylboronic acid in water, showing that complex 1, containing two mutually cis NHC-sulfonate ligands, has better catalytic activity. The activity shown by complex 1 is good, but nonetheless its efficiency is lower than the best systems reported in the literature for nonaqueous Suzuki-Miyaura coupling reactions,22 but compares well with the best catalysts used in neat water.5,7 We believe that our study constitutes a new approach to the preparation of Pd-based water-soluble efficient catalysts and may contribute to the implementation of C-C bond coupling aqueous catalysis.

Experimental Section General Procedures. Compound 1a,17 bis(imidazol-1-yl)methane,23 and 2,6-bis(imidazol-1-yl)pyridine24 were prepared according to literature methods. All the other reagents are commercially available and were used as received. All reactions were carried out under nitrogen using standard Schlenk techniques. NMR spectra were recorded on Varian Innova 300 and 500 MHz spectrometers, using D 2O as solvent. Electrospray mass spectra (ESI-MS) were recorded on a Micromass Quatro LC instrument, and nitrogen was employed as drying and nebulizing gas. High-resolution mass spectra (HR-MS) were recorded on a Q-TOF Premier instrument. Elemental analyses were carried out in an EA 1108 CHNS-O Carlo Erba analyzer. The catalytic experiments were carried out using degassed Milli-Q water. Synthesis of 1. A solution of N,N0 -(methyl)(propanesulfonate)imidazolium (1a, 182 mg, 0.892 mmol), Pd(OAc)2 (100 mg, 0.446 mmol), and KI (148 mg, 0.892 mmol) in degassed DMSO (5.0 mL) was heated at 80 °C during 12 h and then at 160 °C for a further 3 h. During this time the reaction solution turned bright orange from being initially red. The remaining DMSO was removed in vacuo at 60 °C to give an orange solid. The crude solid was washed three times with hot methanol to give the desired product as a pure orange solid. Yield: 277 mg, 75%. 1H NMR (D2O, 300 MHz): δ 7.18 (s, 2H, CHimid), 7.13 (s, 2H, CHimid), 4.40 (m, 4H, NCH2), 3.85 (s, 6H, NCH3), 2.96 (m, 4H, CH2CH2SO3), 2.47 (m, 4H, CH2CH2SO3). 13C(1H) NMR (D2O, 125 MHz): δ 163.9 (NCN), 123.9 (Cimid), 122.4 (Cimid), 49.4 (NCH2CH2CH2SO3), 48.9 (NCH3), 38.2 (NCH2CH2CH2SO3), 25.4 (NCH2CH2CH2SO3). Electrospray HR-MS (20 V, m/z): 638.9065 [M - I]-, 766.8188 [M þ H]-. Anal. Calcd (%) for C14S2O6N4H22PdI2K2 (844.90): C, 19.90; H, 2.62; N, 6.63. Found: C, 20.12; H, 2.95; N, 7.3. Synthesis of 2a. The preparation of compound 2a was carried out by reaction of bis(imidazolyl)methane and 1,3-propane sultone, under different reaction conditions than those reported in the literature.25 A suspension of bis(imidazolyl)methane (500 mg, (22) So, C. M.; Yeung, C. C.; Lau, C. P.; Kwong, F. Y. J. Org. Chem. 2008, 73, 7803. Navarro, O.; Marion, N.; Mei, J. G.; Nolan, S. P. Chem.;Eur. J. 2006, 12, 5142. Marion, N.; Navarro, O.; Mei, J. G.; Stevens, E. D.; Scott, N. M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101. Navarro, O.; Marion, N.; Oonishi, Y.; Kelly, R. A.; Nolan, S. P. J. Org. Chem. 2006, 71, 685. (23) Diezbarra, E.; Delahoz, A.; Sanchezmigallon, A.; Tejeda, J. Heterocycles 1992, 34, 1365. (24) Caballero, A.; Diez-Barra, E.; Jalon, F. A.; Merino, S.; Tejeda, J. J. Organomet. Chem. 2001, 617, 395. (25) Papini, G.; Pellei, M.; Lobbia, G. G.; Burini, A.; Santini, C. Dalton Trans. 2009, 6985.

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Figure 1. Time course for the Suzuki-Miyaura reaction of 4-chloroacetophenone and 4-chlorotoluene with phenylboronic acid using catalyst 1 (1 mol %) in H2O/iPrOH. Solid lines refer to yields. The dotted line refers to conversion of 4-chlorotoluene. 3.37 mmol) and 1,3-propane sultone (2.06 g, 16.9 mmol) in CH3CN was heated at 100 °C during 12 h in a Pyrex tube. The so-generated solid was collected by filtration and washed subsequently with CH2Cl2 and MeOH. Compound 2a was isolated as a white, air- and moisture-stable solid. Yield: 1085 mg, 82%. Synthesis of 2. Compound 2a (129.4 mg, 0.330 mmol), Pd(OAc)2 (75 mg, 0.330 mmol), and KI (109.6 mg, 0.660 mmol) were placed together in a Schlenk tube and dissolved in degassed DMSO (5.0 mL). The mixture was heated at 80 °C during 2 h and then at 140 °C for a further 12 h. The solvent was removed in vacuo at 60 °C to give an orange solid. The crude solid was dissolved in hot methanol (3
10 mL) and transferred to a column chromatograph packed with CH2Cl2/ MeOH (1:1). Elution with CH2Cl2/MeOH (1:9) afforded the separation of a yellow band that contained 2. Yield: 78.6 mg, 29%. 1H NMR (D2O, 300 MHz): δ 7.54 (d, 3JH-H = 2.0 Hz, 2H, CHimid), 7.24 (d, 3JH-H = 2.0 Hz, 2H, CHimid), 6.61 (d, 2 JH-H = 13.5 Hz, 1H, CHbridge), 6.27 (d, 2JH-H = 13.5 Hz, 1H, CHbridge), 3.92 (m, 2H, NCH2), 3.56 (m, 2H, NCH2), 2.61 (m, 4H, CH2CH2SO3), 2.01 (m, 4H, CH2CH2SO3). 13C(1H) NMR (D2O, 75 MHz): δ 169.3 (NCN), 123.2 (Cimid), 122.3 (Cimid), 64.1 (NCH2N), 49.3 (NCH2CH2CH2SO3), 47.9 (NCH2CH2CH2SO3), 26.6 (NCH2CH2CH2SO3). Electrospray HR-MS (20 V, m/z): 622.8752 [M - I]-. The compound was very hygroscopic, and satisfactory analysis could not be obtained. Synthesis of 3a. A suspension of 2,6-bis(imidazol-1-yl)pyridine (530 mg, 2.51 mmol) and 1,3-propane sultone (1.53 g, 12.6 mmol) in CH3CN was heated at 100 °C during 12 h in a Pyrex tube. The so-generated solid was collected by filtration and washed subsequently with CH2Cl2 and MeOH. Compound 3a was isolated as a white, air- and moisture-stable solid. Yield: 972 mg, 85%. 1H NMR (D2O, 300 MHz): δ 9.94 (s, 2H, NCHN), 8.50 (t, 3JH-H = 8.1 Hz, 1H, CHpyr), 8.42 (s, 2H, CHimid), 8.07 (d, 3JH-H = 8.1 Hz, 2H, CHpyr), 7.90 (s, 2H, CHimid), 4.62 (t, 3JH-H = 7.2 Hz, 4H, NCH2), 3.08 (t, 3JH-H=7.2 Hz, 4H, CH2CH2SO3), 2.51 (t, 3JH-H=7.2 Hz, 4H, CH2CH2SO3). 13C(1H) NMR (D2O, 75 MHz): δ 145.84 (NCHN), 145.04 (Cortho), 135.33 (Cpara), 123.86 (Cimid), 120.10 (Cimid), 115.09 (Cmeta), 49.00 (NCH2CH2CH2SO3), 47.48 (NCH2CH2CH2SO3), 25.17 (NCH2CH2CH2SO3). Electrospray MS (20 V, m/z): 334.2 [M - C3H6SO3]þ. Anal. Calcd (%) for C17H21N5S2O6 (455.51): C, 44.83; H, 4.65; N, 15.37. Found: C, 44.64; H, 4.32; N, 14.21. Synthesis of 3. Compound 3a (304 mg, 0.67 mmol), Pd(OAc)2 (150 mg, 0.67 mmol), and KI (111.2 mg, 0.67 mmol) were placed together in a Schlenk tube and dissolved in degassed DMSO (5.0 mL). The mixture was subsequently heated at 80 °C for 2 h and at 140 °C for 12 h. The solvent was removed in vacuo at 60 °C to give an orange solid. The crude solid was dissolved in the minimum amount of water and transferred to a column chromatograph packed with CH2Cl2/MeOH (1:1). Elution with MeOH afforded the separation of an orange band that contained compound 3. Yield: 87.2 mg, 18%. 1H NMR (D2O, 300 MHz): δ 8.29

(t, 3JH-H = 8.1 Hz, 1H, CHpyr), 7.87 (d, 3JH-H = 2.1 Hz, 2H, CHimid), 7.55 (d, 3JH-H = 8.4 HZ, 2H, CHpyr), 7.38 (d, 3 JH-H = 2.1 Hz, 2H, CHimid), 4.33 (m, 4H, NCH2CH2CH2SO3), 2.89 (m, 4H, NCH2CH2CH2SO3), 2.07 (m, 4H, NCH2 CH2CH2SO3). 13C(1H) NMR (D2O, 75 MHz): δ 166.5 (NCN), 149.7 (Cortho), 147.2 (Cpara), 124.7 (Cimid), 118.3 (Cimid), 108.9 (Cmeta), 50.9 (NCH2CH2CH2SO3), 47.5 (NCH2CH2CH2SO3), 27.1 (NCH2CH2CH2SO3). Electrospray HR-MS (20 V, m/z): 685.8862 [M]-. Synthesis of 4. Silver triflate (7.0 mg, 0.027 mmol) was added to a stirred solution of complex 3 (17.7 mg, 0.025 mmol) in MeOH (5.0 mL). Pyridine (1.0 mL) was then added, and the resulting solution was heated at reflux overnight. The reaction mixture was filtered through Celite. Removal of the volatiles yielded complex 4 as a pale yellow solid. Yield: 15.6 mg, 98%. 1H NMR (D2O, 300 MHz): δ 9.14 (d, 3JH-H = 5.1 Hz, 2H, CHpyr), 8.37 (t, 3 JH-H = 8.4 Hz, 1H, CHpyr), 8.25 (t, 3JH-H = 8.1 Hz, 1H, CHpyr), 7.94 (d, 3JH-H = 2.1 Hz, 2H, CHimid), 7.85 (t, 3JH-H = 7.5 Hz, CHpyr), 7.67 (d, 3JH-H=8.1 Hz, 2H, CHpyr), 7.36 (d, 3JH-H = 8.1 Hz, 2H, CHimid), 3.41 (t, 3JH-H = 7.5 Hz, 4H, NCH2CH2CH2SO3), 2.42 (t, 3JH-H =7.5 Hz, 4H, NCH2CH2CH2SO3), 1.86 (m, 4H, NCH2CH2CH2SO3). 13C(1H) NMR (D2O, 75 MHz): δ 172.8 (Cpyr), 167.9 (NCN), 152.7 (Cpyr), 151.5 (Cpyr), 128.5 (Cpyr), 123.7 (Cimid), 118.4 (Cimid), 109.2 (Cpyr), 82.1 (Cpyr), 49.1 (NCH2CH2CH2SO3), 47.7 (NCH2CH2CH2SO3), 26.5 (NCH2CH2CH2SO3). Electrospray HR-MS (20 V, m/z): 581.9175 [M - pyr þ Na]þ. Anal. Calcd (%) for C22S2O6N6H24Pd (639.01): C, 41.55; H, 3.79; N, 13.15. Found: C, 41.23, H, 3.61, N, 14.6. General Procedure for the Suzuki-Miyaura Cross-Coupling Reaction. In a typical run, a Pyrex tube was charged with aryl halide (1 mmol), phenylboronic acid (1.2 mmol), K2CO3 (1.5 mmol), and catalyst (1, 10-1, 10-2, 10-3 mol %). The activation of aryl chlorides required the addition of 1.5 mmol of TBABr as phase transfer catalyst. The solids were dissolved in 5 mL of degassed Milli-Q water or in a degassed 1:1 mixture of Milli-Q water/iPrOH. The reaction mixture was then vigorously stirred at 110 °C. After the desired reaction time, the solution was allowed to cool. The reaction mixture was extracted with dichloromethane (3
5 mL), and the organic phase dried over Na2SO4. The solvent was removed by evaporation to give a crude product. The reaction mixture was analyzed by gas chromatography using anisole as internal standard.

Acknowledgment. We gratefully acknowledge financial support from the Ministerio de Ciencia e Innovaci on of Spain (CTQ2008-04460) and Bancaixa (P1.1B2007-04). We also thank the Ramon y Cajal Program (M.P.). C.S. thanks the Ministerio de Ciencia e Innovaci on for a fellowship. The authors are grateful to the Serveis Centrals d’Instrumentaci o Cientı´ fica (SCIC) of the Universitat Jaume I for providing us with spectroscopic facilities.