Dinuclear Copper(I) Complexes as Precatalysts in Ullmann and

In spite of the drastic experimental conditions required for classic Ullmann and Goldberg ... The first, obvious election could be bis(pyrazolyl)metha...
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Organometallics 2009, 28, 3815–3821 DOI: 10.1021/om900119r

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Dinuclear Copper(I) Complexes as Precatalysts in Ullmann and Goldberg Coupling Reactions ‡  Estela Hald on,† Eleuterio Alvarez, M. Carmen Nicasio,*,† and Pedro J. Perez*,† †

Laboratorio de Cat alisis Homog enea, Departamento de Quı´mica y Ciencia de los Materiales, Unidad Asociada al CSIC, Campus de El Carmen s/n, Universidad de Huelva, 21007 Huelva, Spain, and ‡ Instituto de Investigaciones Quı´micas, CSIC-Universidad de Sevilla, Avenida de Am erico Vespucio 49, 41092 Sevilla, Spain Received February 14, 2009

The use of structurally well-characterized copper(I) species as precatalysts in C-N and C-S bond forming reactions is described. Two new dinuclear Cu(I) complexes containing two isomeric ligands of bis(7-azaindolyl)methane have been synthesized and fully characterized by NMR and X-ray diffraction studies. Both copper(I) species exhibit a 1:1 Cu/L ratio and have been used as precatalysts in the Narylation of 2-pyrrolidinone and S-arylation of thiols with aryl iodides. The complexes efficiently catalyze these cross-coupling reactions, affording high yields of products under mild conditions. of heterocycles7 or amides8 using Pd-based catalysts is still limited.

Introduction Metal-catalyzed cross-coupling reactions have emerged as a powerful tool for the formation of C-C and Cheteroatom bonds with palladium as the metal of choice for such transformations.1 The early examples of crosscoupling chemistry, copper-promoted N-arylation of aromatic amines, the Ullmann reaction (eq 1),2 and the related copper-promoted N-arylation of amides, the Goldberg reaction (eq 2),3 have been known for more than a century. In spite of the drastic experimental conditions required for classic Ullmann and Goldberg condensations such as high reaction temperatures, extended reaction times, and large amounts of copper, these reactions have been widely used for the synthesis of important industrial intermediates.4 The development by the groups of Buchwald5 and Hartwig6 of more versatile and efficient methodologies based on palladium and phosphane ligands for the catalytic formation of aromatic C-N bonds has overshadow Cu-catalyzed cross-coupling chemistry. However, the Pd-catalyzed amination has also encountered significant restrictions in scope. For example, the N-arylation

During the past few years, there has been a renewed interest in the copper-assisted coupling between aryl halides and heteroatom-centered nucleophiles.9 This research has been stimulated by the discovery that the addition of certain chelating ligands accelerates the rate of Ullmann-type reactions.10 Ligands most often used to overcome the aforementioned deficiencies of classical Ullmann-Goldberg chemistry are displayed in Figure 1 and include phenantrolines (I),10c,10d,11 1,2-diamines (II and III),12 R-aminoacids (IV),13 imino-pyridines (V),14 and β-diketones (VI).15,16

*Corresponding authors. E-mail: [email protected]; perez@ dqcm.uhu.es. (1) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A, Diederich, F. Eds.; Wiley-VCH: Weinheim, Germany, 2004. (2) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382. (3) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691. (4) Lindley, J. Tetrahedron 1984, 40, 1433. (5) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed. 1995, 34, 1348. (6) Louie, J.; Hartwig, J, F. Tetrahedron Lett. 1995, 36, 3609. (7) (a) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653. (b) Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F. Angew. Chem. Int. Ed. 2005, 44, 1371. (8) (a) Shakespeare, W. C. Tetrahedron Lett. 1999, 40, 2035. (b) Ying, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101. (c) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Zappia, G. Org. Lett. 2001, 3, 2539. (d) Artamkina, G. A.; Sergeev, A. G.; Beletskaya, I. P. Tetrahedron Lett. 2001, 42, 4381. (e) Ying, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043.

(9) (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (b) Beletskaya, I. P.; Chepakrov, A. V. Coord. Chem. Rev. 2004, 248, 2337. (c) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054. (d) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2008, 47, 3096. (10) (a) Marcoux, J.-F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 10539. (b) Goodbrand, H. F.; Hu, N.-X. J. Org. Chem. 1999, 64, 670. (c) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657. (d) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998, 120, 12459. (11) (a) Gujadhur, R. K.; Bates, C. G.; Vekataraman, D. Org. Lett. 2001, 3, 4315. (12) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727. (b) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421. (13) (a) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453. (14) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem.;Eur. J. 2004, 10, 5607. (15) Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R. P.; Reider, P. J. Org. Lett. 2002, 4, 1623.

r 2009 American Chemical Society

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Figure 1. Most common ligands employed for copper-assisted cross-coupling chemistry.

Despite the improvements in achieving milder reaction conditions and extension of scope by using new types of nucleophiles and aryl halides, Cu-catalyzed cross-coupling chemistry has a major drawback: the lack of understanding of the role of ligands during the catalytic process. Unlike Pd-catalyzed chemistry, only few mechanistic studies have been undertaken with Cu-assisted processes,17 but a precise mechanistic proposal has not been established yet. The best studied reaction is the N-arylation of amides, the Goldberg reaction, in the presence of the Cu(I)/diamine catalytic system. Synthetic work,17a,18 kinetic studies on catalytic and stoichiometric reactions,17a,18 and computational data18a,19 have supported that diamine-ligated Cu(I) amidate complexes are chemically and kinetically competent to serve as intermediates in such arylation processes. The reactive three-coordinated Cu(I) amidate intermediate synthesized and characterized18 in these studies contains only one molecule of the chelating diamine ligand coordinated to the Cu(I) center. However, in most publications on copper-catalyzed cross-coupling chemistry, reactions have been carried out using in situ-formed catalysts from a suitable copper source and excess chelating ligand. Thus, an M/L ratio of 1:2 or even higher20 has been typically used to achieve high yields of coupling products. The above mentioned kinetic studies17a,18b performed with the Goldberg reaction have supported the role of the chelating diamine ligand in controlling the concentration of active catalytic species, but the use of excess ligand requires removal from the crude product. The alternative of using well-defined copper precursors can avoid the inconvenience of ligand removal from reaction mixtures and also the competition between the ligand and the nucleophile in the arylation process, a side reaction observed in some Ullmann-type condensations.12,21 Moreover, the use of precatalysts with a 1:1 Cu/L ratio could reduce the number of copper-based (16) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742. (17) (a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4120. (b) Ouali, A.; Spindler, J.-F.; Jutand, A.; Taillefer, M. Adv. Synth. Catal. 2007, 349, 1906. (c) Ouali, A.; Taillefer, M.; Spindler, J.-F.; Jutand, A. Organometallics 2007, 26, 65. (d) Altman, R. A.; Koval, E. D.; Buchwald, S. L. J. Org. Chem. 2007, 72, 6190. (e) Kaddouri, H.; Vicente, V.; Ouali, A.; Ouazzani, F.; Taillefer, M. Angew. Chem. Int. Ed. 2009, 48, 333. (f) Mansour, M.; Giacovazzi, R.; Ouali, A.; Taillefer, M.; Jutand, A. Chem. Commun. 2008, 6051. (18) (a) Tye, J. W.; Weng, Z.; Johns, A. M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 9971. (b) Strieter, E. R.; Bhayana, B.; Buchwald, S. L J. Am. Chem. Soc. 2009, 131, 78. (19) Zhang, S.-L.; Liu, L.; Fu, Y.; Guo, Q.-X. Organometallics 2007, 26, 4546. (20) (a) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581. (b) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742. (c) Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3490. (d) Cai, Q.; Zou, B.; Ma, D. Angew. Chem. Int. Ed. 2006, 45, 1276. (e) Xia, N.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 337. (f) Xia, N.; Taillefer, M. Chem.;Eur. J. 2008, 14, 6037. (g) Jones, K. L.; Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O. Org. Lett. 2008, 10, 797. (21) (a) Hennessy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4, 269. (b) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684. (c) Enguehard, C.; Allouchi, H.; Gueiffier, A.; Buchwald, S. L. J. Org. Chem. 2003, 68, 4367. (d) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164. (e) Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett. 2007, 9, 3469.

Figure 2. Ligands used in this work.

species with different catalytic activities present in reaction mixtures. Although the use of structurally characterized NHC-Pd(II) has been successfully applied in palladium cross-coupling chemistry,22 such an approach is yet underdeveloped in related copper-assisted reactions, with only a few examples being reported to date.23 With this goal in mind, we have focused our attention on the development of new catalytic systems for C-heteroatom bond forming reactions based on the use of well-defined Cu(I) complexes bearing bis(heterocycle)methane ligands, with a 1:1 Cu/L ratio. In this study, we report the synthesis and Xray characterization of new dinuclear Cu(I) derivatives that contain bis(7-azaindolyl)methane and iodide bridge ligands and describe their use as precatalysts in N-arylation of amides and S-arylation of thiols. To the best of our knowledge, bis (heterocycle)methane ligands have not been tested before in copper-assisted cross-coupling chemistry.

Results and Discussion Synthesis and Characterization of Complexes [(Lsym)CuI]2 [L =bis(7-azaindenyl)methane (symmetric)] and [(Lasym)CuI]2 [Lasym =bis(7-azaindenyl)methane (asymmetric)]. In recent years, our group has been studying the behavior of cationic Cu(I) complexes of composition [TpmXCu(NCMe)] PF6, which contain tris(pyrazolyl)methane ligands (TpmX), in catalytic carbene and nitrene transfer reactions carried out in ionic liquid or under biphasic conditions.24 Since these derivatives meet the requirement of a 1:1 copper to ligand ratio, we decided to explore the catalytic capabilities of [Tpm*Cu(NCMe)]BF425 (Tpm*=HC(3,5-Me2-pyrazolyl)3), 1, in the N-arylation of pyrrolidone. Given that steric hindrance of ligands seems to disfavor Ullmann- and Goldberg-type condensations,9 we decided to investigate the effect of less bulky ligands instead. The first, obvious election could sym

(22) Marion, N.; Nolan, S. P. Acc. Chem. Res. 2008, 41, 1440. (23) (a) Gujadhur, R.; Venkataraman, D. Synth. Commun. 2001, 31, 2865. (b) Gujadhur, R.; Venkataraman, D.; Kintigh, J. T. Tetrahedron Lett. 2001, 42, 4791. (c) Gujadhur, R.; Bates, G. C.; Venkataraman, D. Org. Lett. 2001, 3, 4315. (d) Jerphagnon, T.; van Klink, G. P. M.; de Vries, J. G.; van Koten, G. Org. Lett. 2005, 7, 5241. (e) Pu, Y.-M.; Ku, Y.-Y-; Grieme, T.; Henry, R.; Bhatia, A. V. Tetrahedron Lett. 2006, 47, 149. (f) Niu, J.; Zhou, H.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem. 2008, 19, 7814. (g) Daly, S.; Haddow, M. F.; Orpen, A. G.; Rolls, G. T. A.; Wass, D. F.; Wingad, R. L. Organometallics 2008, 27, 3196. (24) (a) Rodrı´ guez, P.; Caballero, A.; Nicasio, M. C.; Perez, P. J. Org.  Lett. 2006, 8, 557. (b) Rodrı´ guez, P.; Alvarez, E.; Nicasio, M. C.; Perez, P. J. Organometallics 2007, 26, 6661. (c) Cano, I.; Nicasio, M. C.; Perez, P. J. Dalton Trans. 2009, 730.

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Figure 3. Molecular structures of 2 (left) and 3 (right). Thermal ellipsoids are drawn at the 50% probability level. H atoms have been omitted for clarity. Selected bond lengths (A˚) and bond angles (deg) for 2: I(1)-Cu(1)=2.7160(5), I(2)-Cu(1)=2.6704(5), Cu(1)N(4)=2.057(3), Cu(1)-N(2)=2.065(2), N(4)-Cu(1)-N(2)=109.79(10), N(4)-Cu(1)-I(2)=109.89(7), N(4)-Cu(1)-I(1)=113.07(7), I(2)-Cu(1)-I(1)=101.323(15). Selected bond lengths (A˚) and bond angles (deg) for 3: I(1)-Cu(1)=2.6942(4), I(2)-Cu(1) = 2.6517(4), Cu(1)-N(4A)=2.054(2), Cu(1)-N(1A)=2.062(2), N(4A)-Cu(1)-N(1A)=108.39(8), N(4A)-Cu(1)-I(2)=107.64(6), N(1A)-Cu(1)I(2)=106.78(6), N(4A)-Cu(1)-I(1)=112.64(6), N(1A)-Cu(1)-I(1)=111.54(6), I(2)-Cu(1)-I(1)=109.610(12).

be bis(pyrazolyl)methane ligands, but it has been reported that these derivatives favor ligand disproportionation reactions leading to the formation of bis-chelating Cu(I) cationic species and linear dihalocopper(I) anion.26 Therefore, we were encouraged to use bis(heterocycle) methane ligands, as they had not been tested in copper-crosscoupling reactions before. A few years ago the group of Wang27 reported the synthesis of two isomers of bis(7-azaindenyl)methane ligands (Figure 2). We found bis(7-azaindolyl)methanes interesting ligands because upon coordination to a single copper metal center they could form a somewhat uncommon eight-atom chelate ring.28 Moreover, the isomeric structures of Lsym and Lasym would allow the study of the influence of the difference in donor properties of the nitrogen atoms of these ligands on the catalytic coupling processes. The reaction of equimolar amounts of CuI and the ligand Lsym or Lasym in acetonitrile at room temperature afforded the dinuclear Cu(I) complexes [LCuI]2, 2 and 3, in quantitative yields (eq 3). MeCN

L þ Cul f 1=2½LCul2 rt

ð3Þ

L ¼ Lsym or Lasym Complexes 2 and 3 precipitated from the reaction mixture as white, 2, or canary-yellow, 3, air-stable solids. Both derivatives were insoluble in common organic solvents, being sparingly soluble in acetonitrile or in DMSO. The 1H NMR spectra in DMSO-d6 of 2 and 3 displayed only resonances due to ligands Lsym and Lasym that appeared shifted to the downfield region as compared to those of the free ligands, as an indication of their coordination to the copper center. IR spectra showed the absence of any absorption due to coordinated MeCN. In addition, both complexes showed a 1:1 L/Cu ratio as indicated by elemental analysis. Whether bis(7-azaindenyl)methane (25) Reger, D. L.; Collins, J. E.; Rheingold, A. L.; Liable-Sands, L. M. Organometallics 1996, 15, 2029. (26) (a) Fujisawa, K.; Noguchi, Y.; Miyashita, Y.; Okamoto, K.; Lehnert, N. Inorg. Chem. 2007, 47, 10607. (b) Shaw, J. L.; Cardon, T. B.; Lorigan, G. A.; Ziegler, C. J. Eur. J. Inorg. Chem. 2004, 1073.

ligands were coordinated to a single copper ion or bridged to two copper centers could not be inferred from solution NMR studies. To determine the molecular structures of 2 and 3, X-ray diffraction studies were carried out with single crystals of both complexes that were obtained from concentrated acetonitrile solutions. Figure 3 displays the structures of complexes and a list of selected bond distances and angles. Compounds 2 and 3 are dimeric complexes with each of the bis(7-azaindenyl)methane ligands coordinated only to a single copper center, forming eightatom chelate rings. Each Cu(I) ion is surrounded by two nitrogen atoms of the chelating ligand and two bridging iodine atoms in a distorted tetrahedral geometry (angles of 109.79(10)° and 101.323(15)° for 2 and 108.39(8)° and 109.610(12)° for 3). The Cu-N bond distances are within the range found for related structures.28c,29 While this article was being prepared, Buchwald et al.18b structurally characterized a related dimeric complex formed upon mixing CuI and 1,2-cyclohexanediamine. It is interesting to note that the Cu(I)/1,2-diamine catalytic system has been applied to a variety of C(aryl)-N bond formations including the N-arylation of amides,12 N-arylation of heterocycles,21b,30b and also cyanation30a and halogen exchange reactions.30b Catalytic Activities of Complexes 2 and 3 in C-N Bond Formation Reactions. Our initial investigation on coppermediated cross-coupling reactions started by exploring the catalytic activity of cationic compound [Tpm*Cu(NCMe)]PF6, 1, which contains the tris(3,5-Me2-pyrazolyl)methane (27) Song, D.; Schmider, H.; Wang, S. Org. Lett. 2002, 4, 4049. (28) (a) Flinzner, K.; Stassen, A. F.; Mills, A. M.; Spek, A. L.; Haasnoot, J. G.; Reedijk, J. Eur. J. Inorg. Chem. 2003, 671. (b) Schuitema, A. M.; Engelen, M.; Koval, I. A.; Gorter, S.; Driessen, W. L.; Reedijk, J. Inorg. Chim. Acta 2001, 324, 57. (c) van Albada, G. A.; Smeets, W. J. J.; Spek, A. L.; Reedijk, J. Inorg. Chim. Acta 2000, 299, 35. (d) van Albada, G. A.; Smeets, W. J. J.; Spek, A. L.; Reedijk, J. Inorg. Chim. Acta 1999, 288, 220. (e) Sheu, S.-C.; Tien, M.-J.; Cheng, M.-C.; Ho, T.-I.; Peng, S.-M. J. Chem. Soc., Dalton Trans. 1995, 3503. (29) (a) Shimazaki, Y.; Nogami, T.; Tani, F.; Odani, A.; Yamauchi, O. Angew. Chem., Int. Ed. 2001, 40, 3859. (b) Raubenheimer, H. G.; Cronje, S.; Kruger, G. J.; Olivier, P. J. Polyhedron 1995, 14, 2389. (30) (a) Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 2890. (b) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 5578.

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ligand, Tpm*, in the N-arylation of amides.12,14,23g,31 We chose 1,3-dimethyl-5-iodobenzene and 2-pyrrolidinone (eq 4) as the model system to optimize the reaction conditions (Table 1). The desired arylated product was formed in 64%

Table 2. Coupling of ArI with 2-Pyrrolidinone in the Presence of 2 and 3a

Table 1. Optimization Studies for the Cu-Catalyzed N-Arylation of 2-Pyrrolidinonea entry

precatalyst

solvent

base

yield (%)b

1 2 3 4 5 6 7

1 toluene K2CO3 0 27 1 dioxane K2CO3 64 1 dioxane K3PO4 38 1 MeCN K3PO4 85 2 dioxane K3PO4 88 3 dioxane K3PO4 0 none dioxane K3PO4 a Reaction conditions: 3,5-dimethyl-5-iodobenzene (1 mmol), 2-pyrrolidinone (1.2 mmol), base (2 mmol), copper complex (5 mol % of copper, 0.05 mmol for 1, 0.025 mmol for 2 and 3), solvent (1 mL). b Isolated yields (average of two runs).

yield carrying out the reaction in dioxane, in the presence of 5 mol % of the copper and using K3PO4 as the base. Among the bases studied, K3PO4, K2CO3, and Cs2CO3, the former provided the best results. The solvents toluene, acetonitrile, and DMF were less effective than dioxane. A blank experiment showed that in the absence of copper catalyst no arylated product was formed. Moreover, in none of reactions were the homocoupled and dehalogenated products observed. Therefore, the optimal reaction conditions for the N-arylation of 2-pyrrolidinone employed 5 mol % of Cu(I) complex and 2 equiv of K3PO4 with respect to the aryl iodide in dioxane at 110 °C.

Under these conditions, complexes 2 and 3 induced the desired coupling reaction in high yields (85% and 88%, respectively, entries 5 and 6 in Table 1). To extend the scope of this procedure, the N-arylation of pyrrolidinone was carried out using different aryl iodides (Table 2). The nonactivated, parent iodobenzene produced quantitative yields of the arylated product for both catalytic systems (Table 2, entry 1). Further experiments were performed in an effort to find the optimal reaction time and precatalyst loading. Good yields of 80% and 73% (Table 2, entry 2) were obtained after 12 h of reaction, although a trace amount of the starting aryl iodine was detected by GC. In addition, lowering the catalyst loading to 2.5 mol % (half of the initial amount) led to incomplete consumption of reacting benzene iodine after 24 h of reaction. Different phenyl halides were also tested, but no C-N coupling products were observed for bromoand chlorobenzene derivatives, the reaction being selective toward iodides. As shown in entries 3-7, electron-deficient and electron-rich p-substituted aryl iodides were suitable for (31) For other examples on copper-mediated N-arylation of amides see: (a) Crawford, K. R.; Padwa, A. Tetrahedron Lett. 2002, 43, 7365. (b) Padwa, A.; Crawford, K. R.; Rashatasakhon, P.; Rose, M. J. Org. Chem. 2003, 68, 2609. (c) Altenhoff, G.; Glorius, F. Adv. Synth. Catal. 2004, 346, 1661. (d) Deng, W.; Wang, Y.-F.; Zou, Y.; Liu, L.; Guo, Q.-X. Tetrahedron Lett. 2004, 45, 2311. (e) Chen, Y.-J.; Chen, H.-H. Org. Lett. 2006, 8, 5609. (f) Yuan, X.; Xu, X.; Zhou, X.; Yuan, J.; Mai, L.; Li, Y. J. Org. Chem. 2007, 72, 1510.

a Reaction conditions: ArI (1 mmol), 2-pyrrolidinone (1.2 mmol), K3PO4 (2 mmol), copper complex (0.025 mmol, 5 mol % of copper), solvent (1 mL), 110 °C, 24 h. b Isolated yields (average of two runs). c Reaction time: 12 h.

this reaction, providing N-arylated products in good to excellent yields. In addition, this procedure worked well for a sterically hindered substrate such as 2-iodoanisole, which furnished the coupling product in 93% and 97% yield for 2 and 3, respectively (entry 8). The chemoselectivity of these systems toward iodides was exploited to couple effectively aryl iodine and pyrrolidinone in the presence of bromo and chloro substituents on the aryl ring (entries 3 and 4, Table 2). Finally, it should be pointed out that the different electronic nature of the N-donor atoms in compounds 2 and 3 does not seem to have a significant influence on these N-arylation processes. It is interesting to note that these results are comparable with those already described in the literature using in situ-generated catalysts. This methodology presents the advantage of avoiding the separation of free ligand in the final reaction mixture. Interestingly, NMR studies carried out with the final reaction mixture did not show free ligand. Catalytic Activities of Complexes 2 and 3 in C-S Bond Formation Reactions. The formation of C(aryl)-S bonds is of great importance since aryl sulfides are intermediates in the preparation of valuable compounds in biological, pharmaceutical, and material sciences.32 Unlike copper-mediated C-N and C-O cross-coupling, the related C-S bond forming reactions have been comparatively less studied.9 Few examples have appeared recently regarding the use of (32) (a) Jones, D. N. In Comprehensive Organic Chemistry; Barton, D. H., Ollis, D. W., Eds.; Pergamon: New York, 1979; Vol. 3.(b) Kondo, T.; Mitsudo, T.-A. Chem. Rev. 2000, 100, 3205. (c) Procter, D. J. J. Chem. Soc., Perkin Trans. 1 2001, 335.

Article

copper salts with suitable ligands31e,33 or ligand-free copperassisted protocols34 for the arylation of thiols under relatively mild conditions. In view of the lack of precedent on the use of a well-defined precatalyst for C-S cross-coupling reactions, we were encouraged to examine the performance of complexes 2 and 3 in such Ullmann-type condensations. Thiophenol and phenyl iodide (eq 5) were selected as representative substrates to screen the experimental conditions, using precatalyst 2. Initially, the best conditions found for the N-arylation of pyrrolidinone (see above) were ineffective, affording no diphenyl thioether product (Table 3, entry 1). Further experiments revealed a dependence of the S-arylation of thiophenol on the nature of the base. We found that bases such as K3PO4 and K2CO3 (entries 1 and 2) proved to be unsuccessful in furnishing the desired compound, whereas stronger bases such as LiOtBu, NaOtBu, or KOtBu (entries 3-6) afforded the diphenyl thioether in good to excellent yields, the former providing the highest yield. No reaction took place in the absence of the copper complex. However, the undesired phenyl disulfide (C6H5-S-SC6H5) was observed as a minor product in less than 5% yield. In order to eliminate its formation, an experiment was carried out changing the iodobenzene to thiophenol ratio from 1:1.2 to 1.2:1, that is, using a slight excess of the aryl iodide instead. To our delight, diphenyl thioether compound was obtained in quantitative yields (based on the sulfur source) as the only product (entry 6). Since the decrease to 2.5 mol % of 2 avoided the completion of this reaction within 24 h (entry 7), the optimal reaction conditions for the S-arylation of thiophenol were fixed at 5 mol % of the copper precatalysts, dioxane as the solvent at 110 °C, and 2 equiv of LiOtBu.

Subsequently, these conditions were applied to the arylation of other thiols with different aryl iodides. The protocol proved suitable to prepare different thioethers in 76-99% yields, as shown in Table 4. In general, yields did not vary significantly between the reaction of the aryl iodides and thiophenol with changing the electronic nature of the substituent on the aryl iodide (entries 3-6). Like in the N-arylation of pyrrolidone (see above), full selectivity toward iodo derivatives was highlighted in the coupling of 1-bromo- or 1-chloro-4-iodobenzene with thiophenol, affording the corresponding 4-bromo- or 4-chlorophenyl phenyl thioether as the only product (entries 3 and 4). Also, (33) (a) Palomo, C.; Oiarbide, M.; L opez, R.; G omez-Bengoa, E. Tetrahedron Lett. 2000, 41, 1283. (b) Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002, 4, 2803. (c) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517. (d) Zhu, D.; Xu, L.; Wu, F.; Wan, B. Tetrahedron Lett. 2006, 47, 5781. (e) Verma, A. K.; Singh, J.; Chaudhary, R. Tetrahedron Lett. 2007, 48, 7199. (f) Carril, M.; SanMartin, R.; Domı´ nguez, E.; Tellitu, I. Chem.;Eur. J. 2007, 13, 5100. (g) Xin, L.; Bao, W. J. Org. Chem. 2007, 72, 3863. (h) Xu, H.-J.; Zhao, X.-Y.; Deng, J.; Fu, Y.; Feng, Y.-S. Tetrahedron Lett. 2009, 50, 434. (34) (a) Rout, L.; Sen, T. K.; Punniyamurthy, T. Angew. Chem., Int. Ed. 2007, 46, 5583. (b) Ranu, B. C; Saha, A.; Jana, R. Adv. Synth. Catal. 2007, 349, 2690. (c) Rout, L.; Saha, P.; Jammi, S.; Punniyamurthy, T. Eur. J. Org. Chem. 2008, 640. (d) Sperotto, E.; van Klink, G. P. M.; de Vries, J. G.; van Koten, G. J. Org. Chem. 2008, 73, 5625. (e) Buranaprasertsuk, P.; Chang, J. W. W.; Chavarisi, W.; Chan, P. W. H. Tetrahedron Lett. 2008, 49, 2023. (f) Xu, H.-J.; Zhao, X.-Y.; Fu, Y.; Feng, Y.-S. Synlett 2008, 3063.

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Table 3. Optimization Studies for the Arylation of Thiophenol Catalyzed by 2a entry

base

yield (%)b

1 2 3 4 5 6 7 8

K3PO4 0 0 K2CO3 t 93 LiO Bu t 66 NaO Bu 66 KOtBu 99c LiOtBu t LiO Bu 78d LiOtBu 0e a Reaction conditions: ArI (1 mmol), thiophenol (1.2 mmol), base (2 mmol), copper complex (0.025 mmol, 5 mol % of copper), dioxane (1 mL), 110 °C, 24 h. b Isolated yields (average of two runs). c With ArI (1.2 mmol) and thiophenol (1.0 mmol). d With 2.5 mol % of 2 (0.0125 mmol). e In the absence of copper complex.

the reaction was tolerant to the presence of a functional group in the ortho position of the aryl iodine as shown in Table 4, entries 7 and 8, for ortho-substituted aryl iodides. Finally, both copper precatalysts were found to be efficient in the coupling reaction of phenyl-methanethiol, an aliphatic thiol, and 1-methoxy-4-iodobenzene, furnishing the C-S cross-coupling product in high yields (entry 6).

Conclusions The majority of reported systems on copper-assisted crosscoupling chemistry are based on in situ-formed catalysts by reacting a suitable copper salt and excess chelating donor ligand. However, recent studies on the mechanism of copperassisted arylation of amides suggest that active species contain only one molecule of the chelating donor ligand attached to the copper center. This result has been the starting point for the work carried out in this paper. Thus, we have developed an efficient methodology for the formation of C-N and C-S bonds based on the use of well-defined copper(I) precatalysts. We have used in this study two new dinuclear copper(I) complexes of bis(7-azaindolyl)methane ligands, to the best of our knowledge the first reported bis (heterocycle)methane systems used in this way. Both catalytic systems allow the high-yielding arylation of nitrogen and sulfur nucleophiles by using only a 1:1 metal to ligand ratio. Moreover, the experimental conditions described are comparable to those reported for in situ-formed catalysts. Noteworthy is that this methodology does not require the removal of excess ligand from the crude product and prevents its competitive arylation during the reaction course. Furthermore, the use of well-defined catalytic precursors with a 1:1 Cu/L ratio can reduce the amount of possible catalytic species with varied activities formed by using copper salt/L mixtures. We believe the control of the Cu/L ratio could be important for mechanistic studies on copper-catalyzed arylation reactions, in particular for a better understanding of the role of the ligand in such transformation. Work aimed to that purpose is currently underway in our laboratory.

Experimental Section General Methods. All reactions and manipulations were carried out under an oxygen-free nitrogen atmosphere with standard Schlenk techniques. All substrates were purchased from Aldrich. Solvents were dried and degassed before use. [Tpm*Cu(NCMe)]BF425 and bis(7-azaindolyl)methane ligands27 were prepared according to literature procedures. NMR spectra were recorded on a Varian Mercury 400 MHz spectrometer.

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Table 4. Coupling of ArI with Thiols in the Presence of 2 or 3 as Precatalystsa

a Reaction conditions: ArI (1.2 mmol), thiophenol (1.0 mmol), LiOtBu (2 mmol), catalyst 2 or 3 (0.025 mmol, 5 mol %), dioxane (1 mL), 110 °C, 24 h. b Isolated yields (average of two runs).

1

H NMR shifts were measured relative to deuterated solvent peaks but are reported relative to tetramethylsilane. IR data were collected in a Varian Scmitar 1000 Fourier transform IR spectrophotometer. Gas chromatography (GC) data were collected with a Varian GC-3900 chromatograph with a flame ionization detector. Elemental analyses were performed in Unidad de Analisis Elemental of the Universidad de Huelva. Synthesis of [LsymCuI]2, 2. To a stirred solution of CuI (0.1 g, 0,53 mmol) in acetonitrile (10 mL) was added a solution of the ligand bis(7-azaindolyl)methane, Lsym (0.13 g, 0.53 mmol), in acetonitrile (5 mL). The precipitation of a pale yellow solid was immediately observed. The mixture was stirred for 2 h, and complex 2 was filtered, dried under vacuum, and obtained as a pale yellow solid (0.20 g, 91%). 1H NMR (400 MHz, DMSOd6): δ 8.66 (sa, 2H, aza), 8.11 (d, 2H, JHH=7.8 Hz, aza), 8.05 (d, 2H, JHH=3.9 Hz, aza), 7.23 (m, 4H, aza and CH2), 6.65 (d, 2H, JHH = 3.4 Hz, aza). 13C{1H} NMR (100 MHz, DMSO-d6): δ 144.6, 143.2, 130.1, 129.5, 117.9, 101.3 (aza), 50.4 (CH2). Anal. Calcd for C30H24N8Cu2I2 3 2NCMe: C, 42.55; H, 3.13; N, 14.60. Found: C, 42.30; H, 3.10; N, 14.35 (aza=7-azaindolyl). Synthesis of [LasymCuI]2, 3. The above procedure using Lasym as the ligand afforded 3 as a canary-yellow solid (0.21, 95%). 1 H NMR (400 MHz, DMSO-d6): δ 8.84 (d, 1H, JHH=6.3, aza), 8.73 (d, 1H, JHH=4.4 Hz, aza), 8.41 (d, 1H, JHH=7.3 Hz, aza), 8.15 (m, 2H, aza), 7.84 (br s, 1H, aza), 7.60 (br s, 2H, CH2), 7.28 (dd, 1H, JHH=6.3 and 4.4 Hz, aza), 7.24 (dd, 1H, JHH=7.3 and 6.3 Hz, aza), 6.74 (d, 1H, JHH=3.4 Hz, aza), 6.60 (br s, 1H, aza). 13 C{1H} NMR (100 MHz, DMSO-d6): δ 145.2, 144.3, 144.2, 134.6, 133.0, 131.1, 129.8, 128.8, 122.4, 118.1, 117.1, 111.3, 103.0, 102.1 (aza), 57.8 (CH2). Anal. Calcd for C30H24N8Cu2I2 3

2NCMe: C, 42.55; H, 3.13; N, 14.60. Found: C, 42.58; H, 3.03; N, 14.87 (aza=7-azaindolyl). General Catalytic Procedure for the N-Arylation of Pyrrolidinone with Aryl Iodides. The catalyst (0.05 mmol) was dissolved in dioxane (1 mL) in an ampule. The aryl iodide (1.0 mmol), 2-pyrrolidinone (1.2 mmol), and the base, K3PO4 (2 mmol), were added under a nitrogen atmosphere. The reaction was stirred at 110 °C for 24 h in an oil bath. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (15 mL), and centrifuged for 5 min. The clean solution was evaporated to dryness, and the residue was purified by flash chromatography on silica gel. N-(4-Aminophenyl)-2-pyrrolidinone. Following the general procedure, 2-pyrrolidinone (1.2 mmol) was coupled with 4iodoaniline (1.0 mmol) using either of the copper complexes 2 or 3 and K3PO4 (2 mmol) in dioxane (1 mL). The crude residue was purified by flash chromatography on silica gel using ethyl acetate as eluent, affording the product as a brown solid. Yield: 72 % (for 2) and 71% (for 3). 1H NMR (400 MHz, CDCl3): δ 7.31 (d, 2H, JHH=8.6 Hz, CH(Ar)), 6.72 (d, 2H, JHH=8.6 Hz, CH(Ar)), 3.84 (t, 2H, JHH = 7.0 Hz, CH2(pyrr)), 3.66 (s, 2H, NH2), 2.63 (t, 2H, JHH = 8.0 Hz, CH2(pyrr)), 2.10 (q, 2H, JHH =7.5 Hz, CH2(pyrr)). 13C{1H} NMR (100 MHz, CDCl3): δ 174.1 (CO), 143.9, 131.0, (Cq), 122.3 115.5 (CH), 49.6, 32.7, 18.3 (CH2(pyrr)). Anal. Calcd for C10H12N2O: C, 68.18; H, 6.82; N, 15.91. Found: C, 68.03; H, 6.98; N, 15.47 (Ar=aryl; pyrr= pyrrolidinone). N-(4-Trifluoromethylphenyl)-2-pyrrolidinone. Following the general procedure, 2-pyrrolidinone (1.2 mmol) was coupled with 4-iodotrifluoromethylbenzene (1.0 mmol) using either

Article of the copper complexes 2 or 3 and K3PO4 (2 mmol) in dioxane (1 mL). The crude residue was purified by flash chromatography on silica gel using ethyl acetate as eluent, affording the product as a white crystalline solid. Yield: 99 % (for 2) and 93% (for 3). 1 H NMR (400 MHz, CDCl3): δ 7.73 (d, 2H, JHH =8.6 Hz, CH (Ar)), 7.61 (d, 2H, JHH =8.6, CH(Ar)), 3.88 (t, 2H, JHH =7.1, CH2(pyrr)), 2.63 (s, 2H, NH2), 2.63 (t, 2H, JHH = 8.1 Hz, CH2(pyrr)), 2.16 (q, 2H, JHH = 7.8 Hz, CH2(pyrr)). 13C{1H} NMR (100 MHz, CDCl3): δ 174.9 (CO), 142.6 (Cq), 126.1 (q, JCF=3.8 Hz, CH), 126.0 (q, JCF=33.7 Hz, Cq), 124.3 (q, JCF = 271.6, Cq), 119.3 (CH), 48.6, 33.0, 18.0 (CH2(pyrr)). Anal. Calcd for C11H10NF3O: C, 57.64; H, 4.37; N, 6.11. Found: C, 57.51; H, 4.37; N, 6.35. General Catalytic Procedure for the S-Arylation of Thiols with Aryl Iodides. The catalyst (0.05 mmol) was dissolved in dioxane (1 mL) in an ampule. The aryl iodide (1.2 mmol), the thiol (1.0 mmol), and the base, LiOtBu (2 mmol), were added under a nitrogen atmosphere. The reaction was stirred at 110 °C for 24 h in an oil bath. The reaction mixture was allowed to cool to room temperature and treated with ethyl acetate (15 mL) and water (5 mL). The organic and aqueous layers were then separated, and the organic layer was evaporated to dryness. The residue was purified by flash chromatography on silica gel. Crystal data for 2:. C34H30Cu2I2N10 [C30H24Cu2I2N8, 2(C2H3N)] , Mw = 959.56, a single crystal of suitable size, yellow block (0.18  0.10  0.09 mm3) crystallized from acetonitrile, coated with dry perfluoropolyether, mounted on a glass fiber, and fixed in a cold nitrogen stream [173(2) K] to the goniometer head; monoclinic, space group C2/c (no. 15), a=17.4128(16) A˚ b= 10.8076(10) A˚, c=18.4692(17) A˚, β=107.9660(10)°, V = 3381.0(5) A˚3, Z = 4, Fcalcd = 1.885 g cm-3, λ(Mo KR1) = 0.71073 A˚, F(000)=1872, μ=3.126 mm-1; 57 433 reflections were collected from a Bruker-Nonius X8Apex-II CCD diffractometer in the range 4.48° < 2θ < 61.36°, and 5134 independent reflections [R(int)=0.0504] were used in the structural analysis. The data were reduced (SAINT) and corrected for Lorentz polarization effects and absorption by the multiscan method applied by SADABS.35,36 The structure was solved by direct methods (SIR-2002)37 and refined against all F2 data by full-matrix least-squares techniques (35) Bruker. Apex 2, version 2.1; Bruker AXS Inc.: Madison, WI, 2004. (36) Bruker. SAINT and SADABS; Bruker AXS Inc.: Madison, WI, 2001.

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(SHELXL97)38 converged to final R1 =0.0324 [I>2σ(I)], and wR2=0.0935 for all data, with a goodness-of-fit on F2, S=1.028, and 219 parameters. Crystal data for 3:. C34H30Cu2I2N10 [C30H24Cu2I2N8, 2(C2H3N)], Mw = 959.56, a single crystal of suitable size, yellow block (0.18  0.130.11 mm3) crystallized from acetonitrile, coated with dry perfluoropolyether, mounted on a glass fiber, and fixed in a cold nitrogen stream [173(2) K] to the goniometer head; monoclinic, space group C2/c (no.15), a = 17.9884(5) A˚, b = 9.8693(3) A˚, c = 19.9941(6) A˚, β = 107.9660(10)°, V = 3376.53(17) A˚3, Z = 4, Fcalcd=1.888 g cm-3, λ(Mo KR1)=0.71073 A˚, F(000)=1872, μ= 3.131 mm-1; 35 249 reflections were collected from a Bruker-Nonius X8Apex-II CCD diffractometer in the range 4.76°