Indenylidene Ruthenium Complex Bearing a Sterically Demanding

Mar 25, 2009 - Indenylidene Ruthenium Complex Bearing a Sterically Demanding NHC Ligand: An Efficient Catalyst for Olefin Metathesis at Room ...
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Organometallics 2009, 28, 2848–2854

Indenylidene Ruthenium Complex Bearing a Sterically Demanding NHC Ligand: An Efficient Catalyst for Olefin Metathesis at Room Temperature Herve´ Clavier,*,† Ce´sar A. Urbina-Blanco,† and Steven P. Nolan*,† Institute of Chemical Research of Catalonia (ICIQ), AV Països Catalans 16, 43007 Tarragona, Spain ReceiVed January 29, 2009

The synthesis and characterization of a novel indenylidene-containing ruthenium catalyst bearing the N-heterocyclic carbene (NHC) ligand 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene (SIPr) are reported. Comparative reactivity studies with other indenylidene complexes using various substrates show the importance of the sterically demanding SIPr ligand on catalyst reaction profile. The investigation of the reaction scope for ring-closing metathesis transformations establishes the influence of the NHC on catalyst activity especially as a function of substrate steric bulk. The novel catalyst was found very efficient at room temperature for nonsterically hindered substrates. Since the new catalyst was found to be soluble in a variety of solvents, a number of these were examined to gauge the importance of solvent effects. Introduction Olefin metathesis represents one of the most useful and versatile tools in organic synthesis for the formation of carbon-carbon double bonds.1 One fascinating feature of olefin metathesis is the access to numerous variations on the theme achieved as a function of both substrates and reaction conditions. As a testimony, this synthetic strategy is now employed to access fine chemicals, biologically active compounds, new functionalized materials, and various polymers.2 Diverse metal-based complexes can catalyze these transformations. However, the rapid development of this area has been punctuated by groundbreaking developments specifically focusing on well-defined ruthenium-carbene complexes (Figure 1). Among these, benzylidene catalysts3 are most widely used. Much effort has been aimed at tuning these structures: L ligand screening (mainly phosphines4 and N-heterocyclic carbenes5), pyridine derivatives6 * To whom correspondence should be addressed. E-mail: sn17@ st-andrews.ac.uk. † Present address: School of Chemistry, University of St-Andrews, St Andrews KY16 9ST, U.K. (1) For reviews on metathesis, see: (a) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3013–3043. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29. (c) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003; p 1204. (d) Astruc, D. New J. Chem. 2005, 29, 42–56. (e) Deshmukh, P. H.; Blechert, S. Dalton Trans. 2007, 2479– 2491. (2) For reviews on synthetic applications, see: (a) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199–2238. (b) McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R. Chem. ReV. 2004, 104, 2239–2258. (c) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490–4527. (d) Van de Weghe, P.; Bisseret, P.; Blanchard, N.; Eustache, J. J. Organomet. Chem. 2006, 691, 5078–5108. (e) Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew. Chem., Int. Ed. 2006, 45, 2664–2670. (f) Gradillas, A.; Pe´rezCastells, J. Angew. Chem., Int. Ed. 2006, 45, 6086–610. (g) Hoveyda, A. H.; Zhugralin, A. R. Nature (London) 2007, 450, 243–251. (h) Kotha, S.; Lahiri, K. Synlett 2007, 2767–2784. (i) Compain, P. AdV. Synth. Catal. 2007, 349, 1829–1846. (3) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2039–2041. (b) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100–110. (c) Roberts, A. N.; Cochran, A. C.; Rankin, D. A.; Lowe, A. B.; Schanz, H.-J. Organometallics 2007, 26, 6515–6518. (4) For selected references, see: (a) Dias, E. L.; Nguyen Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887–3897. (b) Love, J. A.; Sanford, M. S.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 10103–10109.

Figure 1. Ruthenium-based olefin metathesis catalysts (L ) neutral ligand; X ) anionic ligand).

or anionic ligands,7 development of “boomerang”8 and related supported catalysts,9 etc. (5) (a) N-Heterocyclic Carbenes in Synthesis; Nolan, S. P., Ed.; WileyVCH: Weinheim, 2006; p 304. (b) N-Heterocyclic Carbenes in Transition Metal Catalysis; Glorius, F., Ed.; Springer-Verlag: Berlin, 2007; p 231. (c) Colacino, E.; Martinez, J.; Lamaty, F. Coord. Chem. ReV. 2007, 251, 726– 764. (6) (a) Sanford, M. S.; Love, J. A.; Grubbs, R. H. Organometallics 2001, 20, 5314–5318. (b) Love, J. A.; Sanford, M. S.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002, 41, 4035–4037. (c) P’Pool, S. J.; Schanz, H.-J. J. Am. Chem. Soc. 2007, 129, 14200–14212. (7) (a) Sanford, M. S.; Henling, L. M.; Day, M. W.; Grubbs, R. H. Angew. Chem., Int. Ed. 2000, 39, 3451–3453. (b) Conrad, J. C.; Parnas, H. H.; Snelgrove, J. L.; Fogg, D. E. J. Am. Chem. Soc. 2005, 127, 11882– 11883. (c) Monfette, S.; Fogg, D. E. Organometallics 2006, 25, 1940– 1944. (8) For selected references, see: (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791–799. (b) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168–8179. (c) Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. 2002, 41, 794–796. (d) Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. 2002, 41, 2403–2405. (e) Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem., Int. Ed. 2002, 41, 4038–4040. (f) Michrowska, A.; Bujok, R.; Harutyunyan, S.; Sashuk, V.; Dolgonos, G.; Grela, K. J. Am. Chem. Soc. 2004, 126, 9318–9325. (g) Bieniek, M.; Bujok, R.; Cabaj, M.; Lugan, N.; Lavigne, G.; Arlt, D.; Grela, K. J. Am. Chem. Soc. 2006, 128, 13652–13653. (h) Rix, D.; Caijo, F.; Laurent, I.; Boeda, F.; Clavier, H.; Nolan, S. P.; Mauduit, M. J. Org. Chem. 2008, 73, 4225– 4228. (9) Clavier, H.; Grela, K.; Kirschning, A; Mauduit, M.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 6786–6800.

10.1021/om900071t CCC: $40.75  2009 American Chemical Society Publication on Web 03/25/2009

Indenylidene Ru Complex with a NHC Ligand

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Figure 2. Indenylidene-ruthenium complexes.

In spite of these efforts, few structurally diverse complexes, such as alkenylcarbene,10 vinylidene,11 allenylidene,12 and indenylidene13 compounds, have proven competent in mediating olefin metathesis transformations (Figure 1). As an alternative to benzylidene catalysts, indenylidene-ruthenium catalysts are especially attractive due to their straightforward synthesis from [RuCl2(PPh3)3] and 1,1-diphenylpropargyl alcohol.14 Some of these complexes recently developed are now commercially available.15 Moreover, these latter compounds were found to be more resistant to harsh reaction conditions (temperature and functional group tolerance) than their benzylidene counterparts.16 Nevertheless, modifications of the indenylidene scaffold have been scarcely examined, especially when it comes to the influence of the N-heterocyclic ligand (NHC) ligand. Recently, we reported that the ruthenium complex bearing the bulky NHC 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr), 4, exhibits a better activity in cross-metathesis reactions than their analogues bearing the tricyclohexylphosphine 1, 1,3-bis(2,4,6trimethylphenyl)imidazol-2-ylidene (IMes), 2, and 1,3-bis(2,4,6trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes), 3 (Figure 2).17 Although no satisfying explanation has been purposed so far, several studies point out that a complex bearing a saturated NHC such as SIMes allows for improved performance compared to its unsaturated NHC-containing counterpart.17-19 (10) (a) Nguyen, S. T.; Johnson, L. K.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1992, 114, 3974–3975. (b) Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1993, 115, 9858–9859. (c) Wilhelm, T. E.; Belderrain, T. R.; Brown, S. N.; Grubbs, R. H. Organometallics 1997, 16, 3867–3869. (d) Gandelman, M.; Rybtchinski, B.; Ashkenazi, N.; Gauvin, R. M.; Milstein, D. J. Am. Chem. Soc. 2001, 123, 5372–5373. (11) (a) Werner, H.; Stark, A.; Schulz, M.; Wolf, J. Organometallics 1992, 11, 1126–1130. (b) Gru¨nwald, C.; Gevert, O.; Wolf, J.; Gonza´lezHerrero, P.; Werner, H. Organometallics 1996, 15, 1960–1962. (c) Wolf, J.; Stru¨er, W.; Werner, H.; Schwab, P.; Schulz, M. Angew. Chem., Int. Ed. 1998, 37, 1124–1126. (d) Castarlenas, R.; Eckert, M.; Dixneuf, P. H. Angew. Chem., Int. Ed. 2005, 44, 2576–2579. (12) (a) Fu¨rstner, A.; Picquet, M.; Bruneau, C.; Dixneuf, P. H. Chem. Commun. 1998, 1315–1316. (b) Picquet, M.; Bruneau, C.; Dixneuf, P. H. Chem. Commun. 1998, 2249–2250. (c) Fu¨rstner, A.; Liebl, M.; Lehmann, C. W.; Picquet, M.; Kunz, R.; Bruneau, C.; Touchard, D.; Dixneuf, P. H. Chem.-Eur. J. 2000, 6, 1847–1857. (13) For reviews, see: Boeda, F.; Clavier, H.; Nolan, S. P. Chem. Commun. 2008, 2726–2740. (14) (a) Harlow, K. J.; Hill, A. F.; Wilton-Ely, J. D. E. T. Chem. Soc., Dalton Trans. 1999, 285–291. (b) Fu¨rstner, A.; Hill, A. F.; Liebl, M.; Wilton-Ely, J. D. E. T. Chem. Commun. 1999, 601–602. (15) Complexes 1, 2, and 3 and other ruthenium-indenylidene complexes are now commercially available from Strem, Umicore, and Evonik Degussa. (16) Clavier, H.; Petersen, J. L.; Nolan, S. P. J. Organomet. Chem. 2006, 691, 5444–5447. (17) Boeda, F.; Bantreil, X.; Clavier, H.; Nolan, S. P. AdV. Synth. Catal. 2008, 350, 2959–2966. (18) Clavier, H.; Nolan, S. P. Chem.-Eur. J. 2007, 13, 8029–8036.

For these reasons, we hypothesized that substitution of IPr by its saturated analogue 1,3-bis(2,6-diisopropylphenyl)-4,5dihydroimidazol-2-ylidene (SIPr) might lead to improved catalyst activity. Here we report the synthesis and characterization of indenylidene-ruthenium 5 bearing the sterically demanding SIPr.20 Investigation of its catalytic performance was examined by studying ring-closing metathesis (RCM) of dienes and enynes. Various solvents were evaluated as reaction medium with the aim to increase activity of the catalyst and find a more environmentally friendly solvent than dichloromethane.

Results and Discussion Synthesis and Characterization of Catalyst. Treatment of tricyclohexylphosphine indenylidene-ruthenium 1 with 2 equiv of SIPr led to the substitution of one of the phosphines by the NHC ligand. After 3 h at 70 °C, the reaction was found to be complete by 31P NMR spectroscopy and the volatiles were removed in Vacuo. The diverse attempts to purify the crude mixture by crystallization techniques failed. Thus, [(SIPr)RuCl2(PCy3)(Ind)] complex 5 was purified by silica gel chromatography using technical grade pentane and ether, giving 84% yield of a microcrystalline red solid. Of note, the synthesis of 5 was scaled to 10 g in this manner with yields reaching 80%. The 1H NMR spectrum of 5 showed a characteristic resonance at 4 ppm for the imidazolidine protons. The 13C NMR spectrum displayed characteristic low-field resonances for the NHC carbenic carbon at around 200 ppm with a 2JC-P of 77 Hz indicating a transarrangement of the phosphine. The signal at 293 ppm is characteristic of a RudC carbenic carbon with a 2JC-P of 10 Hz, indicating, this time, a cis-arrangement of the phosphine. The 31P NMR spectrum showed a single resonance at 22 ppm. Elemental analysis and high-resolution mass spectrometry also confirmed the composition 5. [(SIPr)RuCl2(PCy3)(Ind)], 5, was found perfectly stable in the solid state and could be easily handled in air. However, in solution the stability of 5 was relatively low, similar in fact to its benzylidene analogue.21 In CD2Cl2 at 40 °C, traces of degradation were (19) Ritter, T.; Hejl, A.; Wenzel, A. G.; Funk, T. W.; Grubbs, R. H. Organometallics 2006, 25, 5740–5745. (20) For discussions on stereoelectronic parameters of NHCs, see: (a) Dı´ez-Gonza´lez, S.; Nolan, S. P. Coord. Chem. ReV. 2007, 251, 874–883. (b) Dorta, R.; Stevens, E. D.; Scott, N. M.; Costabile, C.; Cavallo, L.; Hoff, C. D.; Nolan, S. P. J. Am. Chem. Soc. 2005, 127, 2485–2495. (c) Kelly, R. A., III.; Clavier, H.; Giudice, S.; Scott, N. M.; Stevens, E. D.; Bordner, J.; Samardjiev, I.; Hoff, C. D.; Cavallo, L.; Nolan, S. P. Organometallics 2008, 27, 202–210.

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ClaVier et al.

Scheme 1. Synthesis of Indenylidene-Ruthenium Complex Bearing SIPr Ligand 5

observed after 2 h; nevertheless nondegraded 5 was still present after 24 h. In toluene-d8 at 80 °C, degradation occurred after only 1 h and was complete after 24 h. These results are in sharp contrast to those claimed for other indenylidene complexes such as IMes- and IPr-containing catalysts 2 and 4.22 However this strongly suggests that the sterically demanding SIPr improves the phosphine dissociation and should lead to an enhanced initiation rate in catalysis. To unambiguously characterize this complex and to obtain possible insight into fine structural differences between indenylidene complexes, X-ray quality crystals were grown for a saturated solution of 2-propanol at -20 °C. Interestingly, 5 was found to be soluble at room temperature in numerous organic solvents. The structure of Ru-indenylidene complex 5 with a selection of bond distances and angles is presented in Figure 3 as an ORTEP representation. Complex 5 shows the expected distorted square-pyramidal geometry around the metal center with a slight tilt of the NHC (P-Ru-NHC ) 106°). Bond distances and angles were found comparable to those reported for the similar complex 4 bearing IPr,22 with the exception of those related to the NHC, i.e., torsion angle of the NHC backbone and the lengths C-N, which are characteristic of a saturated NHC. Catalyst Comparison on Benchmark Substrates. In order to evaluate the catalytic performance of catalyst 5, RCM

Figure 3. ORTEP plot of complex 5 (drawn with 50% ellipsoids at 50% probability level). Most hydrogen atoms are omitted for clarity. Selected bond lengths (Å) and angles (deg): Ru(1)-C(28) 1.8604(11), Ru(1)-C(15) 2.1019(11), Ru(1)-P(1) 2.4446(3), Ru(1)-Cl(1) 2.3890(3), Ru(1)-Cl(2) 2.3885(3), C(15)-N(1) 1.3551(13), C(15)-N(2) 1.3570(15); C(28)-Ru(1)-C(15) 102.25(4), C(15)-Ru(1)-P(1) 162.13(3), Cl(1)-Ru(1)-Cl(2) 164.373(10), N(1)-C(15)-N(2) 106.30(9); N(1)-C(7)-C(8)-N(2) 25.94(12).

reactions were carried out on different substrate types. The results were compared to those obtained with other rutheniumindenylidene complexes 1-4, to establish a thorough evaluation of the NHC effect.18 The benchmark substrates include various substituted and functionalized dienes and enynes. The reactions were carried out with 2 mol % of catalyst, and reaction times as well as temperatures were optimized (Table 1). As initially hypothesized, 5, bearing the saturated NHC SIPr, was found much more competent than its IPr congener 4. Such differences between saturated and unsaturated NHCs have already been noticed between IMes and SIMes.23 Overall, 5 showed a greater catalytic efficiency for the tested RCM reactions examined with the exception of 10. The cyclization of unhindered or moderately hindered dienes 6, 8, 12, and 14 was achieved in quantitative yields in less than 30 min at room temperature (entries 1, 2, 4, and 5). The RCM reactions of ether 14 and enyne 16, which required a slight thermal activation with (S)IMes-containing catalysts 2 and 3, were accomplished at room temperature in only 15 min with 5 and 1 h with 4 (entries 5 and 6). Comparison with commercially available catalysts 2, 3, and 5 allowed for an important reduction of the cyclization reaction time from 5 h to less than 0.5 h (entries 1, 2, and 4-6). Moreover, 5 gave similar or better isolated yields of products 7 and 15 than the first-generation catalyst 1, which was found more efficient in metathesis transformations of sterically unhindered substrates (entries 1 and 5). Increasing the size of the NHC ligand allows for improving the performance of the indenylidene complex in both accelerating the reaction and reducing the temperature required for the activation step. Thus it appears that the sterically demanding IPr and SIPr improve the phosphine dissociation and consequently the initiation rate. However, the new complex 5 and its counterpart 4 gave poor yields for the RCM of the most sterically hindered substrate 10 (respectively 22% and 41%, entries 3). Reaction Scope. Next, the scope of metathesis transformations catalyzed by the indenylidene complex 5 was investigated. In light of these preliminary results, we investigated the scope using only 1 mol % of 5 as catalyst loading. RCM of various amide-, ester-, and ether-containing substrates were carried out at rt in less than 1 h (Table 2). Of note, when reactions were conducted at 40 °C, it is simply because reactions conducted at 25 °C were found to be too sluggish. The formation of fiveand six-membered rings was also achieved straightforwardly (entries 1, 3, 4, 8, 10, and 11). RCM leading to a sevenmembered ring translated into a substantial increase in the required reaction time (entries 2, 5, 6, 9, and 13). The examination of more challenging substrates revealed that (21) For comparison, stability tests were carried out with complex 5 and its benzylidene analogue bearing SIPr showing a comparable stability. (22) Jafarpour, L.; Schanz, H.-J.; Stevens, E. D.; Nolan, S. P. Organometallics 1999, 18, 5416–5419. (23) For a partial explanation on the activity difference between IMesand SIMes-containing catalysts, see: Occhipinti, G.; Bjørsvik, H.-R.; Jensen, V. R. J. Am. Chem. Soc. 2006, 128, 6952–6964.

Indenylidene Ru Complex with a NHC Ligand

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Table 1. Catalyst Comparison on Model Olefinsa

a Reaction conditions: substrate (0.5 mmol), 2 mol % of [Ru] complex (0.01 mmol), DCM (5 mL, 0.1 M). b Reactions were performed in toluene at 80 °C using 5 mol % of [Ru] (0.025 mmol).

substituted dienes are also well tolerated (entries 7 and 12). Alcohols such as diene 44 are equally compatible with catalyst 5; however after 2 h of reaction at rt only a moderate isolated yield was obtained (65%, entry 14). Since ring-closing enyne metathesis represents a powerful method for the synthesis of exocyclic 1,3-dienes, which can be useful synthons, we extended the reaction scope of 5 to several enynes (Table 3). For substrates 46 and 48, excellent yields were obtained at rt in 15 min using 1 mol % of 5 (entries 1 and 2). On the other hand, the cyclization of 50 was found to be more problematic, and only 14% of the desired product was isolated after 2 h at rt (entry 3), whereas RCM carried out on a similar substrate possessing an additional methyl 52 and following the same reaction conditions led to the formation of 78% of 53 (entry 4). When the substrate required usually harsher reaction conditions, like 54, the SIPr-ruthenium indenylidene 5 was found ineffective at 25 °C (entry 5). We were concerned by the low activity of 5 toward tetrasubstituted diene 10 (Table 1, entry 3) and decided to investigate in more detail this category of substrates (Table 4). First, we focused on tolsylamine-based substrates that are known to be easier to ring close than malonate analogues.18 Regrettably, in

spite of a catalyst loading of 5 mol % and a reaction temperature of 80 °C, the RCM afforded only poor yields of six- and sevenmembered rings, respectively 57 and 59 (entries 1 and 2). Using diene 10 as a model, we attempted to revisit the reaction conditions in changing solvent and temperature (entries 3-6). Since the stability tests performed highlighted the poorer stability of 5, we examined whether the catalyst could be active more than 60 min under catalytic conditions. Whereas 22% of cyclized product 11 was isolated after 5 h, only 5% of 11 was observed after 1 h. This means that the catalyst is not fully degraded and is still efficient after 1 h at 80 °C (entries 3 and 4). Use of either dichloroethane (DCE) instead of toluene or DCM at lower temperature to avoid an accelerated degradation did not allow the isolation of 11 (entries 5 and 6). To gain insight into the reactivity of tetrasubstituted diene, we repeated similar experiments with olefin 60, possessing 1,2-disubstituted C-C double bonds (entry 7-9). Catalyst 5 afforded good results at 80 °C independent of the solvent used (entries 7 and 8), and even at 40 °C in DCM, the RCM occurred and 46% of compound 7 was isolated (entry 9). Thus, we can conclude that the weaker activity of indenylidene 5 toward tetrasubstituted diene is due to the Ψ,Ψ-disubstitution of the two C-C double bonds.

2852 Organometallics, Vol. 28, No. 9, 2009 Table 2. Catalytic Performance of Complex 5 in RCM of Dienesa

ClaVier et al. Table 3. Activity of Complex 5 in RCM of Enynes

a Reaction conditions: substrate (0.5 mmol), 1 mol % of complex 5 (0.005 mmol, 5.2 mg), DCM (5 mL, 0.1 M), 25 °C.

Table 4. Study of RCM of Tetrasubstituted Dienesa

a Reaction conditions: substrate (0.5 mmol), 5 mol % of complex 5 (0.025 mmol, 25.8 mg), solvent (5 mL, 0.1 M). b1H NMR conversion.

a Reaction conditions: substrate (0.5 mmol), 1 mol % of complex 5 (0.005 mmol, 5.2 mg), DCM (5 mL, 0.1 M), 25 °C.

Solvent Effects Study. Recently, a few studies have highlighted that the identity of the solvent can have a significant impact on metathesis reactions. An early report of Grubbs and co-workers disclosed that the initiation rate roughly paralleled the dielectric constant of the reaction medium.24 For this reason, DCM is the solvent commonly used to conduct metathesis reactions. Further investigations reported that, surprisingly, acetic acid or cyclohexane can be more productive solvents than (24) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 6543–6554.

DCM.25 Fluorinated aromatic hydrocarbon solvents were also reported to enhance the performance of metathesis catalysts.26 Since the SIPr-containing indenylidene complex 5 was found to be soluble in numerous organic solvents, we examined various media including chlorinated, fluorinated, hydrocarbon, protic, and aqueous solvents using trisubstituted malonate 8 as a model substrate. Reactions were conducted at rt, with a low catalyst loading (0.5 mol %) in order to slow the RCM reaction, and to obtain an accurate comparison of the solvent effects (Table 5). Under these conditions, after 30 min, excellent to full conversions were reached in DCM, DCE, benzene, toluene, perfluorobenzene, cyclohexane, and diethyl ether (entries 1-6 and 9). Interestingly, all media tested allowed for the formation of product 9; nonetheless protic solvents (water, 2-propanol, and acetic acid), acetonitrile, and dioxane proved unsuitable (conversion inferior to 25%, entries 7 and 13-16). Of note, neither (25) Adjiman, C. S.; Clarke, A. J.; Cooper, G.; Taylor, P. C. Chem. Commun. 2008, 2806–2808. (26) (a) Rost, D.; Porta, M.; Gessler, S.; Blechert, S. Tetrahedron Lett. 2008, 49, 5968–5971. (b) Samojlowicz, C.; Bieniek, M.; Zarecki, A.; Kadyrov, R.; Grela, K. Chem. Commun. 2008, 6282–6284.

Indenylidene Ru Complex with a NHC Ligand

Organometallics, Vol. 28, No. 9, 2009 2853

Table 5. Investigations of Solvent Effect on Catalyst Activitya

Table 6. Solvent Effect at Lower Catalyst Loadinga

entry

solvent

conv (%)b

entry

solvent

conv (%)b

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

DCM DCE benzene toluene C6F6 cyclohexane dioxane THF Et2O CpOEt AcOEt acetone MeCN iPrOH AcOH H2O

97 95 85 84 >98 78 10 48 94 35 30 69 7 25 16 17

1 2 3 4 5 6 7 8

DCM DCE benzene toluene C6F6 cyclohexane Et2O DCM/C6F6 (9:1)

67 67 51 47 87 38 65 70

a

Reaction conditions: substrate (0.5 mmol), 0.5 mol % of complex 5 (0.0025 mmol, 2.6 mg), solvent (5 mL, 0.1 M), 25 °C, 30 min. b 1H NMR conversion, average of two runs.

catalyst 5 or diene 8 is soluble in water, so for the reaction conducted in water, a biphasic mixture was observed with the RCM taking place directly in the substrate (entry 16). We were surprised to not observe polymer formation in this reaction. This suggests that RCM could possibly be conducted in highconcentration conditions, whereas dilute reaction mixtures are commonly used. Reactions carried out in oxygen-containing solvents, for example, acetone and tetrahydrofuran, gave moderate conversions (respectively entries 12 and 8). Since diethyl ether is appropriate for RCM, we examined cyclopentyl ethyl ether, but a low conversion was attained (entry 10). This poor performance is also observed for ethyl acetate (entry 11). Unfortunately, all solvents considered as “preferred” for medicinal chemistry27 were found to be unsuitable for metathesis transformations. Since a number of solvents have been identified as providing appealing RCM rates, we decided to decrease the catalyst loading to 0.1 mol % of 5 for a better comparison of these reaction media (Table 6). Perfluorobenzene was found to provide the higher conversion, 87% in 0.5 h (entry 5). Other solvents tested gave moderate results (entries 1-4, 6, and 7). To explain the beneficial effect of C6F6, we thought that some interaction(s) between the ruthenium center and the fluorine atoms, at it was previously reported for fluorine-containing NHC ligands, might be at play.28 To validate this hypothesis and lower the cost of the reaction,29 an experiment using a mixture of DCM/C6F6 (9: 1) was performed (entry 8). The significant drop in conversion suggests that the enhancement of the catalytic performance of 5 in perfluoro-solvent is due more to its physical properties than to a fluorine-ruthenium interaction. Of note among the seven solvents tested, only toluene and cyclohexane are considered acceptable in medicinal chemistry. (27) (a) Jime´nez-Gonza´lez, C.; Curzons, A. D.; Constable, D. J. C.; Cunningham, V. L. Clean Technol. EnViron. Policy 2005, 7, 42–50. (b) Alfonsi, K.; Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.; Johnson, T. A.; Kleine, H. P.; Knight, C.; Nagy, M. A.; Perry, D. A.; Stefaniak, M. Green Chem. 2008, 10, 31–36. (c) http://www.ich.org/LOB/media/media423. pdf. (28) Ritter, T.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 11768–11769. (29) Hexafluorobenzene is relatively expensive, $2.2 (USD) a gram (from Aldrich).

a Reaction conditions: substrate (0.5 mmol), 0.1 mol % of complex 5 (0.0005 mmol), solvent (5 mL, 0.1 M), 25 °C, 30 min. b 1H NMR conversion, average of two runs.

Conclusion In summary, we have disclosed the synthesis and full characterization of a new ruthenium-indenylidene complex bearing the NHC SIPr, 5. The investigation of its catalytic performance in RCM reactions has shown 5 to be much more competent than its commercially available analogues 1-3 for unhindered and moderately hindered substrates. The use of a more sterically demanding NHC such as SIPr suggests an enhancement of phosphine dissociation and consequently an increase in the initiation rate of metathesis reactions. This catalyst, however, exhibits low activity toward tetrasubstituted diene, more precisely β,Ψ-disubstituted R,ω-diolefins. This is apparently caused by the steric bulk of the NHC, which disfavors the coordination of congested substrates. The solvent screening demonstrated a positive effect of fluorinated aromatic hydrocarbon solvents on the RCM performance. This highlights the need for metathesis transformations in greener reaction media and the development of metathesis catalysts compatible with acceptable solvents for the pharmaceutical industry.

Experimental Section General Considerations. All reagents were used as received. Dichloromethane (DCM) and toluene were dispensed from a solvent purification system from Innovative Technology. Other solvents were dried from molecular sieves. Catalyst synthesis was performed in a MBraun glovebox containing dry argon and less than 1 ppm oxygen. Flash column chromatography was performed on silica gel 60 (230-400 mesh). 1H, 13C, and 31P nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 400 Ultrashield NMR spectrometer. High-resolution mass spectroscopy (HRMS) analyses was performed on a Waters LCT Premier spectrometer or a Waters GCT spectrometer. Elemental analyses were performed at the Universidad Complutense de Madrid. Substrates and products have been previously described: 6-43,30 44,31 45,32 46-51,30 52,33 53,34 54-57,30 58 and 59,35 60.36 Synthesis of [(SIPr)RuCl2(PCy3)(Ind)] (5). In a glovebox, a 100 mL Schlenk flask was charged with a stirring bar, 2 g (2.17 mmol) of 1, 1.76 g (2 equiv, 4.5 mmol) of SIPr carbene, and 50 mL of dry toluene. The reaction mixture was stirred 3 h at 70 °C. (30) Ref 18 and references therein. (31) Kashima, C.; Huang, X. C.; Harada, Y.; Hosami, A. J. Org. Chem. 1993, 58, 793–794. (32) Peters, E. C.; Brown, H. C. J. Am. Chem. Soc. 1975, 97, 7454– 7457. (33) Gibson, S. E.; Hardick, D. J.; Haycock, P. R.; Kaufmann, A. K. C.; Myasaki, A.; Tozer, M. J.; White, A. J. P. Chem.-Eur. J. 2007, 13, 7099– 7109.

2854 Organometallics, Vol. 28, No. 9, 2009 The volatiles were removed in Vacuo, and the remaining solid was purified by silica gel chromatography (pentane/diethyl ether, 95: 5), affording the ruthenium complexes as a red solid; 1.88 g (84% yield). 1H NMR (400 MHz, CD2Cl2): δ 8.89 (d, 3J(H,H) ) 7.0 Hz, 1H, HAr), 7.64 (d, 3J(H,H) ) 7.1 Hz, 2H, HAr), 7.51-7.49 (m, 1H, HAr), 7.46-7.38 (m, 6H, HAr), 7.26 (t, 3J(H,H) ) 7.2 Hz, 1H, HAr), 7.19 (t, 3J(H,H) ) 7.4 Hz, 1H, HAr), 7.10 (d, 3J(H,H) ) 7.0 Hz, 1H, HAr), 6.83 (s, 1H, HAr), 6.81 (d, 3J(H,H) ) 7.7 Hz, 1H, HAr), 6.71 (d, 3J(H,H) ) 6.5 Hz, 1H, HAr), 6.62 (d, 3J(H,H) ) 7.6 Hz, 1H, HAr), 4.39 (septet, 3J(H,H) ) 6.3 Hz, 1H, CH(CH3)2), 4.19-4.10 (m, 2H, CH2-CH2), 4.05-4,00 (m, 1H, CH(CH3)2), 3.91-3.82 (m, 2H, CH2-CH2), 3.62 (sept, 3J(H,H) ) 6.3 Hz, 1H, CH(CH3)2), 3.07 (septet, 3J(H,H) ) 6.3 Hz, 1H, CH(CH3)2), 2.00-1,94 (m, 3H, CHPCy3), 1.75-0.90 (m, 51H, CH3NHC + CH2PCy3), 0.66 (d, 3J(H,H) ) 6.4 Hz, 3H, CH(CH3)2). 13C NMR (100 MHz, CD2Cl2): δ 293.2 (d, J(C,P) ) 9.7 Hz, CH), 200.6 (d, 2 J(C,P) ) 77.2 Hz, C), 149.73 (C), 149.68 (C), 147.2 (C), 146.8 (C), 144.3 (C), 141.1 (C), 138.3 (CH), 137.5 (C), 137.0 (C), 136.7 (C), 136.1 (C), 130.3 (CH), 130.2 (CH), 129.6 (CH), 128.6 (CH), 128.4 (CH), 127.7 (CH), 127.2 (CH), 126.6 (CH), 124.44 (CH), 124.40 (CH), 123.7 (CH), 123.5 (CH), 116.5 (CH), 55.5 (CH2), 55.2 (CH2), 34.1 (CH), 33.9 (CH), 31.3 (CH2), 31.1 (CH2), 29.4 (CH2), 29.1 (CH2), 29.0 (CH2), 28.0 (CH3), 27.9 (CH2), 27.83 (CH2), 27.77 (CH2), 27.74 (CH2), 27.69 (CH2), 27.64 (CH2), 27.3 (CH3), 27.1 (CH3), 26.9 (CH2), 26.6 (CH2), 26.4 (CH2), 25.9 (CH3), 23.4 (CH3), 23.0 (CH3), 22.9 (CH3), 22.3 (CH3), 21.8 (CH3). 31P NMR (162 MHz, CD2Cl2): δ 22.19. HRMS (ESI): m/z calcd for C60H81N2ClPRu: 997.4869 [M+ - Cl]; found 997.4922. Anal. Calcd for C60H81N2Cl2PRu (MW 1033.25): C, 69.75; H, 7.90; N, 2.71. Found: C, 70.05; H, 8.27; N, 2.48. (34) Lee, H.-Y.; Kim, H. Y.; Tae, H.; Kim, B. G.; Lee, J. Org. Lett. 2003, 5, 3439–3442. (35) Yao, Q.; Zhang, Y. J. Am. Chem. Soc. 2004, 126, 74–75. (36) Bhar, S.; Chaudhuri, S. K.; Sahu, S. G.; Panja, C. Tetrahedron 2001, 57, 9011–9016.

ClaVier et al. General Procedure for Metathesis Reaction. A Schlenk apparatus under argon was charged with the substrate (0.5 mmol) and the solvent (5 mL) (DCM for reaction at RT and 40 °C, toluene for reaction at 80 °C), then precatalyst (0.005-0.025 mmol). The progress of the reaction was monitored by TLC. The solvent was removed under vacuum, and the crude residue was purified by flash column chromatography to yield the pure product. Of note, for low catalyst loading experiments a stock solution of the catalyst was used, the reaction was quenched after 30 min by addition of ethyl vinyl ether, and the conversion was determined by 1H NMR spectroscopy by integrating the characteristic signals for allylic proton resonances.

Acknowledgment. Funding for this project was generously provided by the ICIQ Foundation and the EC through the seventh framework program (Grant CP-FP 211468-2-EUMET). Umicore AG is gratefully acknowledged for the generous gift of materials. We thank Dr. Jordi BenetBuchholz and Mr. Eduardo C. Escudero-Ada´n for the X-ray structure determination. Note Added after ASAP Publication. Modifications to the author affiliations, corresponding author footnotes, and Acknowledgment have been made to correct the version that first appeared on the Web March 25, 2009. The version that has now been published on the Web on April 14, 2009, is correct. Supporting Information Available: The CIF file of crystal structure has been deposited with the CCDC, No. CCDC-703796 (5). Copies of the data can be obtained free of charge on applications to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, fax: +44 1223 336 033; http://www.ccdc.cam.ac.uk; e-mail: deposit@ccdc. cam.ac.uk. This material is available free of charge via the Internet at http://pubs.acs.org. OM900071T