Recent developments in design and synthesis of well-defined ruthenium metathesis catalysts – a highly successful opening for intricate organic synthesis

This paper surveys the latest and fast growing developments in the design and synthesis of homogeneous and immobilized ruthenium metathesis catalysts. These novel ruthenium carbene complexes, devised as convenient counterparts of the well-defined tungsten and molybdenum alkylidene complexes, display comparable activity and selectivity in metathesis reactions combined with good tolerance towards organic functionalities, air and moisture. Due to their valuable attributes, they have been applied successfully in a multitude of complex organic and polymer syntheses involving ring-opening


Introduction
During the last decade, olefin metathesis has known a real breakthrough, becoming a powerful synthetic tool in organic and polymer chemistry. 1,2Along these lines, numerous ruthenium complexes, as convenient counterparts of the well-defined tungsten and molybdenum alkylidene complexes, 3,4 have been prepared and used successfully as efficient metathesis catalyst precursors in a wide range of well-established synthetic procedures such as ring-closing metathesis (RCM) (Eq.1), 5 ring-opening metathesis (ROM) (Eq.2), 5 cross-metathesis (CM) (Eq.3), 6 enyne metathesis (EM) (Eq.4), 7 acyclic diene metathesis (ADMET) (Eq.5) 8 and ringopening metathesis polymerization (ROMP) (Eq.6) 9 .Due to the ever increasing potential of these methodologies, new applications have emerged in manufacturing a diversity of natural products, biologically active organic compounds or functional polymers with special architectures. 10

Ruthenium alkylidene complexes
The well-defined ruthenium-carbene complexes 1 and 2, reported by Grubbs and coworkers, 11,12 are the first ruthenium catalysts to show good activity and selectivity in metathesis of acyclic and cyclic olefins while exhibiting an improved tolerance towards various organic functionalities, air and moisture, opening, thus, a new era in metathesis applications in organic and polymer syntheses [13][14][15][16][17] (Scheme 1, where R is isopropyl, phenyl, cyclopentyl or cyclohexyl (Cy) and R′ is methyl or phenyl).9][20][21] An important group of catalysts, therein, consists of ruthenium alkylidene complex 3, bearing a heteroatom-containing carbene, as well as the chelated complexes 4 and 5 developed by Ciba AG, 18,19  A practical advantage offered by these new ruthenium catalysts is that, for the first time, it became possible to use such Ru initiators in ROMP of cycloolefins (e.g.dicyclopentadiene) with the reaction injection molding (RIM) technique, and by immobilization on solid supports.Furthermore, their synthesis is a convenient one-step procedure starting from the ruthenium phosphane benzylidene complex 1.For instance, reaction of two equivalents of complex 1 with one equivalent of phenyl vinyl sulphide affords the ruthenium complex 3, with an S-containing ligand, whereas an equimolar reaction between 1 and 2-(3-butenyl)pyridine leads to the chelated ruthenium complex 4. Likewise, bidentate phosphines with large natural bite angles (e.g. based on xanthene or Cy 2 P(CH 2 ) n PCy 2 , n=3-5) have been obtained from ruthenium complex 1 and 1,ωbis(dicyclohexylphosphine)alkanes (e.g.1,5-bis(dicyclohexylphosphine)pentane). 21The latter bidentate phosphine ligands could also be used to attach ruthenium alkylidene complexes to solid supports as a means of obtaining heterogenized catalysts.

Ru H Cl
To finely tune the activity and stability of the ruthenium alkylidene complexes, further heterocyclic ligands have been incorporated into the ruthenium coordination sphere.Complexes 8 (R = Cy) and 9 (R = Mes, R' = H, Br, NO 2 ) are representative examples. 22,23 Ph H PR 3  Cl Scheme 3. Ruthenium benzylidene complexes with heterocyclic ligands.
Of these two complexes, the bis-pyridine adduct 9 (R' = Br) is an excellent metathesis catalyst possessing a high initiation rate.
Schiff-bases proved to be another class of attractive ligands in creating new ruthenium complexes.They incorporate two donor atoms (N and O) which, on chelation, provide opposite features: the phenolate oxygen atom is a hard donor and will stabilize a higher oxidation state of the ruthenium atom whereas the imine nitrogen is a softer donor and, consequently, will rather stabilize the lower oxidation state of ruthenium.Besides, Schiff-bases are easily accessible through one-step procedures via almost quantitative condensation of common amines with aldehydes.To capitalize on the high potential of Schiff-bases, a wide range of efficient ruthenium catalysts, e.g.10a-f and 11a-f, with O,N-chelated Schiff-base "dangling-ligands", have been prepared by Verpoort and coworkers. 24 In addition, the same research group introduced cationic Ru-benzylidene complexes 12a-f prepared in situ from the corresponding neutral complexes 10a-f, by treatment with one equivalent of silver salts or trimethylsilyl salts (Scheme 5).Schiff-base ligated ruthenium carbenes are appropriate scaffolds for manufacturing immobilized catalysts by means of spacers attached to a silylated solid support.
The portfolio of well-defined ruthenium alkylidene catalysts also includes dinuclear complexes such as 13, easily obtained from RuCl 2 (PPh 3 ) 3 and 1,4-benzene-bis(diazomethane), that provide ready access to particular polymer architectures like ABA block-copolymers by ROMP of cycloolefins 26  Heterobimetallic ruthenium catalysts are also to be mentioned, e.g.compounds 14 and 15, containing both ruthenium and osmium or rhodium, conveniently resulting from reaction of complex 1 with the corresponding diosmium or dirhodium derivatives.Such heterobimetallic complexes were reported to possess significantly enhanced activity in ROMP of 1,5cyclooctadiene and 2,2-bis(trifluoromethyl)norbornene. 27triking progress in the chemistry of ruthenium carbene complexes was achieved through the synthesis by Herrmann et al. of a novel class, the ruthenium benzylidene complexes 16-19, 28,29 obtained via derivatization of the phosphane complex 1.To this end, one or both PCy 3 ligands in 1 have been replaced by the sterically demanding imidazolin-2-ylidenes, easily accessible and known to be more Lewis-basic than PCy 3 .In contrast to phosphane, these non-labile ligands possess strong σ-donor and weak π-acceptor properties stabilizing both the 16-electron precatalysts and the highly electron defficient metathesis intermediates.The approach also allowed control of the reactivity by systematic variation of the R groups in the imidazolin-2ylidene moiety (Scheme 7).In spite of significant differences observed in the reactivity of 16-19, these ruthenium benzylidene complexes bearing N-heterocyclic carbenes (NHC) as ancillary ligands were found to promote conversion of a wide panel of dienes or enynes into the corresponding cyclic compounds by ring closing metathesis (RCM) or enyne metathesis (EM). 30Applications include synthesis of five-, six-, seven-, eight-and higher-membered ring system compounds, of N-and O-heterocyclic compounds (Eq.7-12), as well as of macrocyclic products such as the commercially important perfume ingredient Exaltolid ® .Significantly, compatibility between these ruthenium benzylidene complexes and functional groups in different organic compounds seems to practically match that of the complex 1.An unexpected supplemental advantage of this class of catalysts is their excellent performance in the formation of tri-and even tetra-substituted cycloalkene products by RCM.

Ru Br
At the same time, on applying a similar procedure for ligand exchange in ruthenium carbene complexes, Grubbs and coworkers 31 prepared another series of ruthenium catalysts (20-22)  within the imidazolin-2-ylidene class, using different members of the Arduengo imidazolin-2ylidene ligands 32 (Scheme 8).Synthesis occurs readily by a two-step sequence.In the first step, the imidazolin-2-ylidene carbene ligand is conveniently synthesized from the corresponding salt with sodium hydride in liquid ammonia/THF, and used without purification in the subsequent step involving a ligand exchange reaction in the ruthenium complex 1; the latter reaction is rapid at room temperature, in toluene.The final product was isolated as a pinkish-brown microcrystalline solid that could be purified by recrystallization from pentane at -78°C.Of the numerous 1,3-diaryl-imidazolin-2ylidenes tried by Grubbs, only the 2,6-disubstituted aryls (including the 1,3-dimesitylimidazolin-2-ylidene), which are sufficiently bulky to prevent substitution of the second phosphane ligand, gave clean reaction products.Synthesis and characterization of NHC ruthenium alkylidene complexes were reported simultaneously by the Nolan group as well. 33ery stable and highly selective for cross-metathesis (CM) and ring-closing metathesis (RCM) proved to be the O-chelated NHC ruthenium isopropoxy-benzylidene complex 23, incorporating a 1,3-dimesitylimidazolidin-2-ylidene ligand, prepared by Hoveyda et al. 34 (Scheme 9).Of great interest for asymmetric metathesis chemistry is the family of chiral ruthenium alkylidene complexes.In this juncture, the ruthenium benzylidene complexes 24-26, which use backbone stereogenicity to induce atropisomeric chirality in the unsymmetrical N-aryl substituents, have been synthesized and applied in metathesis reactions. 36,37 Other new chiral ruthenium complexes, 27 and 28, bearing different alkylidene moieties, also have been synthesized and used in enantioselective metathesis reactions. 38Remarkably, over 98% enantioselectivity has been reported when applying complex 27 in ring-opening metathesis of a norbornene derivative and a substituted olefin 38a (Scheme 13).

Ruthenium vinylidene complexes
Ruthenium vinylidene complexes also are having a considerable impact on metathesis related chemistry.However, these complexes showed only moderate metathesis activity in RCM of unsubstituted α,ω-dienes and ROMP of higly strained norbornenes. 40ther interesting cationic and neutral 18-electron ruthenium vinylidene complexes were obtained by Bruce 41a , Osawa 41b (31-33) and van Koten 42 (34-36) and were screened for their metathesis activity, but their applicability remains limited to a small range of olefinic substrates.A substantial improvement was accomplished by Louie and Grubbs through synthesis of ruthenium vinylidene complexes coordinating an imidazolin-2-ylidene ligand. 43Complexes 37 resulted from the bisphosphane ruthenium complex 1 (R = Cy) and free imidazoline carbenes or their salts (Scheme 16).
In this class, complexes possessing both the phosphane and imidazolin-2-ylidene ligands, displayed substantial metathesis activity in RCM of diethyl diallylmalonate yielding substituted cycloolefin, but the reaction rate was slower than that with the corresponding bisimidazolin-2ylidene ruthenium vinylidene complex.As detailed mechanistic investigations on the metathesis reaction by Grubbs and coworkers 43  Indeed, the catalytic activity of 38 proved to be even higher than that of the complex 35, evidencing a higher unsaturation degree in the coordination metal sphere.The pathway for generation of the real catalytically active species, 39, from 38 and the olefin substrate can be seen in Scheme 18.

Ru C C H tBu
Scheme 18.Generation of the active species from catalyst 38.

Ruthenium indenylidene complexes
First, 3-phenyl indenylidene complex 40 was prepared from commercial [RuCl 2 (PPh 3 ) 4 ] and 3,3diphenylpropyn-3-ol as the carbene source.Then, the PPh 3 ligands in complex 40 were readily substituted by the better donating PCy 3 affording the parent indenylidene complex 41.These ruthenium indenylidene complexes have higher thermal stability as compared to the related alkylidene complexes 1 and 2 and also perform well in various ring-closing metathesis reactions.
Substitution of phosphane ligands in complexes 40 and 41 by imidazolin-2-ylidene ligands enabled synthesis of new 16-electron ruthenium indenylidene complexes of even higher activity and stability.Thus, addition of 1,3-dimesitylimidazolin-2-ylidene to the 3-phenylindenylidene complexes 40 and 41, in toluene at room temperature, leads to 43 and 44, respectively, in considerable yield 47  Thermal stability studies indicated that compounds 44 and 46, incorporating a PCy 3 ligand, are very stable and do not decompose even after heating to 80°C for several days.RCM experiments using diethyl diallylmalonate and diallyl tosylamine as substrates showed a good catalytic activity and selectivity of the ruthenium indenylidene complexes of this precatalyst family (yields of 88% and 94% were recorded for 44 and 46, respectively).(Schemes 23 and 24).Interesting ruthenium indenylidene complexes containing Schiff-bases as ligands arise from diphosphane ruthenium indenylidene complexes and aromatic salicylaldimines.For instance, complex 47 has been obtained in high yield from 41 (Scheme 25).
Complex 47 was characterized by means of 1 H, 13 C, 31 P-NMR and elemental analysis and successfully applied in enol-ester synthesis (nucleophilic addition of carboxylic acids to terminal alkynes).Importantly, results obtained with catalyst 47 are comparable with those reported for the best metathesis Ru-catalysts. 49Related Schiff-base ruthenium complexes 48 and 49 have been prepared analogously and their activity tested in ROMP of cycloolefins and ATRP of vinyl monomers 50  In conclusion, we should mention that bidentate Schiff-base ancillary ligands incorporated into this type of complex pronouncedly influence both their activity and stability.
The related arene ruthenium indenylidene complex 50, generated in situ from an allenylidene precursor by treatment with strong acids (e.g., HOTf, HBF 4 ), displayed a high activity in acyclic diene metathesis reaction (ADMET), RCM of diallyl tosylamide, enyne metathesis reaction of allyl propargyl tosylamide and ROMP of cyclopentene and cyclooctene. 51For example, in It is important to point out that in ring-opening metathesis polymerization (ROMP) of cyclooctene with the system [RuCl(p-cymene)(=C=C=CPh 2 )(PCy 3 )][CF 3 SO 3 ]/ HOSO 2 CF 3 , in chlorobenzene, an unexpectedly high yield of polyoctenamer was obtained after a short reaction time at room temperature (Scheme 30), whereas when starting from a less reactive monomer, cyclopentene, a maximum yield of 67% could be reached even after 1 hour at 0°C. 51 PhCl, RT°C, 5min, 97% n

Ruthenium allenylidene complexes
The family of neutral and cationic ruthenium allenylidene complexes is large but up to now only a limited number of its members have been verified as active metathesis catalysts. 52Special attention has been paid to three neutral, coordinatively unsaturated 16-electron ruthenium allenylidene complexes, namely the bisphosphane complex 51, the imidazolin-2-ylidene complex 52 and the binuclear complex 53 whose catalytic efficiency for alkene metathesis reactions has been investigated extensively (Scheme 31). 53,54 C C C Cy Bisphosphane complex 51 is the allenylidene analogue of the Grubbs catalyst 1 with PCy 3 ligands.Its counterpart having PPh 3 groups seems to be rather unstable under normal conditions and to rearrange readily to the indenylidene complex.The more stable but less active, imidazolin-2-ylidene complex 52, an allenylidene analogue of the benzylidene complex 20, stems from complex 51.Binuclear allenylidene complex 53, a highly active metathesis ruthenium complex, is related to the binuclear ruthenium benzylidene complex [Ru 2 Cl 4 (pcymene)(=CHPh)(PCy 3 )] reported by Grubbs and coworkers. 27t variance with the former group of neutral allenylidene complexes, a larger number of cationic, coordinatively saturated 18-electron ruthenium allenylidene complexes have been reported and applied with excellent results in a variety of metathesis reactions. 55Essentially, these allenylidene complexes, e.g., 54-57, contain η 6 -arene ligands associated with additional phosphane and chloride ligands, in conjunction with a "non-coordinating" counterion X - (Scheme 32).By varying the phosphine substituents (R= Ph, Cy, i-Pr), the nature of the counterion X -(X = PF 6 , BPh 4 , BF 4 , OTf, etc) and the terminal groups on the allenylidene moiety (R' = Ph, pchlorophenyl, p-methoxyphenyl, etc), the number of available complexes of this type has been increased.Their potential as metathesis precatalysts was also thoroughly evaluated.

Miscellaneous ruthenium complexes
Two very active cationic ruthenium complexes, 58 and 59, introduced by Werner and coworkers 56 and Hofmann and coworkers 57 should also be mentioned.The former has the structure of a hexacoordinated ruthenium carbyne complex while the latter is a ruthenium vinyl carbene bearing a bidentate phosphane ligand.(

Immobilized ruthenium complexes
Immobilization of ruthenium alkylidene complexes, due to innovative research by Nguyen and Grubbs, 58 using cross-linked polystyrene-divinylbenzene as the solid support, and by Verdonck et al., 59 using a dendrimeric carbosilane core, is a further development in metathesis catalysis.The latter catalysts were manufactured by attaching ruthenium alkylidenes to the boundary of the zero-th generation (G0) and first generation (G1) of the carbosilane dendrimers (Scheme 34).
The catalytic activity of the dendrimeric ruthenium catalyst 60 has been tested in ROMP of norbornene.By means of such complexes, multi-arm star polymers could be produced in a controlled manner.
Barrett and coworkers 60,61 heterogenized bisphosphane ruthenium complex 1 on polystyrene and evidenced that it was possible to use the supported catalyst in RCM of ethyl diallylmalonate and ROMP of norbornene.Highly efficient immobilized catalysts have been obtained from NHC ruthenium alkylidene complexes deposited on various solid supports.For instance, the saturated imidazolin-2-ylidene ruthenium complex 21 has been directly microencapsulated in polystyrene by Barrett 62 and Gibson 63 or anchored on a polystyrene support by Blechert and coworkers. 646][67][68][69][70][71][72] In order to enhance the commercial potential of the above chemical processes, these researchers have achieved synthesis of two multifunctional Schiff-base ruthenium carbene complexes deposited on MCM-41 (61 and 62) thus providing recyclable and efficient solid catalysts 70,71 (Scheme 35).The methodology followed for preparation of the chemically tethered catalyst onto MCM-41 consisted of immobilizing a previously synthesized precursor containing an anchorable functionality.In the case of 61 and 62, the mesoporous silica surfaces were treated with the respective tris(alkoxy)silyl-functionalized complex, a commonly applied procedure to tether organometallic compounds onto solid supports.For the solid supported catalysts 61 and 62 two different routes have been employed. 71Structural examination by Raman spectroscopy, X-ray diffraction, X-ray fluorescence, solid-state NMR and N 2 -adsorption analysis showed that in all cases the anchoring of the homogeneous catalyst via a spacer onto the MCM-41 surface took place through two or three covalent bonds. 69 similar approach has been exploited to synthesize and characterize another new heterogeneous ruthenium catalyst, 63, that exhibited good stability, reusability and leaching characteristics in both ring-closing metathesis of heteroatom containing dienes giving heterocycles and atom transfer radical addition of halogenated alkanes to olefins yielding polyhalogenated alkanes 71,72

Conclusions
During the last decade, the number of ruthenium metathesis catalysts has rapidly expanded owing to their accessibility, remarkable activity and selectivity, encountered generally in conjuction with good tolerance towards polar organic functionalities, air and moisture.A significant advancement in this area was achieved through the introduction of imidazolin-2ylidene ligands into conventional ruthenium alkylidene complexes.Many of these catalytic systems can be prepared conveniently starting from the classical Grubbs' ruthenium benzylidene catalyst.New trends in process development are currently being opened through design and synthesis of immobilized ruthenium catalysts.Ruthenium complexes enjoy an excellent application profile in metathesis reactions, and particularly in ring-closing metathesis (RCM), cross-metathesis (CM), enyne metathesis (EM), ring-opening metathesis (ROM) and ringopening metathesis polymerization (ROMP).
35o alternative synthetic pathways for the ruthenium benzylidene complex 23, employing as precursors different ruthenium alkylidene complexes, have been reported by Blechert et al.35(Scheme 10).Convenient synthesis of ruthenium complexes of the Hoveyda type.

Issue in Honor of Prof. Alexandru T. Balaban ARKIVOC 2005 (x) 105-129 ISSN 1424-6376 Page 116 © ARKAT USA, Inc phosphane
cogently displayed that increased ligand dissociation (i.e. of ) is necessary to accelerate the initiation step and thereby enhance the catalytic activity, a coordinatively unsaturated, phosphane-free ruthenium vinylidene complex 38 might be formed directly in situ from the ruthenium dimer 29, in the presence of a terminal alkyne and the N-heterocyclic carbene (IMes), as such or as its salts.

Issue in Honor of Prof. Alexandru T. Balaban ARKIVOC 2005 (x) 105-129 ISSN 1424-6376 Page 117
The methodology can also use the trisphosphane complex [RuCl 2 (PPh 3 ) 3 ] for synthesis of indenylidene complex 40.It has been proved unequivocally that the initially formed allenylidene Reaction pathway for synthesis of ruthenium indenylidene complex 40.
© ARKAT USA, Inc Scheme 33) Ruthenium carbyne and vinyl carbene catalysts 58 and 59.Catalysts 58 and 59 are easily accessible and display a quite high activity in ring-closing metathesis reactions.