Introduction

Recent decades have seen a burgeoning of interest in olefin metathesis, as witnessed by a rapidly growing number of elegant applications.¹ Using this tool, chemists can now efficiently synthesize an impressive range of molecules that only a decade ago required significantly longer and tedious routes. The development of efficient and selective catalysts 1a-c has been the key to the widespread application of olefin metathesis in organic synthesis.¹

Although the second-generation Grubbs's ruthenium catalyst 1b possesses in general a very good application profile, combining high activity with an excellent tolerance of a variety of functional groups, the phosphine-free catalyst 2b, recently introduced by Hoveyda et al.,^2,3 displays even higher reactivity levels toward electron-deficient substrates, such as acrylonitrile,⁴ fluorinated olefins,⁵ and others.³ Excellent air-stability, ease of storage, and handling and the possibility of catalyst reuse and immobilization⁶ constitute additional advantages of this system.^3,7

Despite the promising application profile observed in reactions of 2b, this catalyst proved to initialize slower than 1b, probably as a result of steric (large isopropoxy group) and electronic factors (iPrO Ru electron donation).⁸ Blechert and Wakamatsu have shown recently that replacement of the isopropoxybenzylidene "ligand" in 2 by BINOL- or biphenyl-based benzylidene results in a large improvement in catalyst activity, as-for example-complex 4b is drastically more reactive not only than 2b but also than the "second-generation" Grubbs's catalyst 1b.^9,10 Recently, we reported on the preparation of two Hoveyda-type complexes substituted at the benzylidene fragment. Catalyst 5, which is very stable and easy to prepare from inexpensive -asarone, shows activity comparable to that of the parent Hoveyda's carbene 2b,¹¹ while the nitro-substituted catalyst 6b possesses a dramatically enhanced reactivity.¹² This observation suggests that decreasing the electron density at the oxygen atom of the ligating iPrO fragment of the Hoveyda-type ruthenium carbene results in increasing its catalytic activity. We reckoned that the electron-withdrawing NO₂ group (EWG) in 6b would weaken iPrO Ru chelation and facilitate initiation of the catalytic cycle.^12-14 Herein we report a more comprehensive investigation on the synthesis, stability, and application profile of the nitro-substituted complexes 6b and 7b, their "first-generation" congeners 6a and 7a, and other variations (8-10, Scheme 2).

	Scheme 1. Family of Ruthenium Catalysts for Alkene Metathesisa a Cy = cyclohexyl; Mes = 2,4,6-trimethylphenyl.
	Scheme 2

Results and Discussion

Design of Catalysts. The discovery of highly active catalysts 4b and 6b prompted us to further investigate the structure-reactivity relationship, in order to fine-tune the catalysts' properties. First, we decided to examine the "pure" electronic effects in the isopropoxybenzylidene sphere of complexes 6 and 7. The design of catalysts 8-10 was based on the idea that decreasing the electron density in the styrene part of 2 and simultaneously applying a steric bulk^9b close to the chelating isopropoxy fragment could result in an even higher increase of catalytic activity (Scheme 2).

Preparation. As illustrated in Scheme 3, we used commercially available nitrosalicylaldehydes 11-13 as starting materials for preparation of the corresponding 2-isopropoxy-5-nitrostyrenes 14-16 via a straightforward alkylation-olefination sequence. Bromination/nitration of phenols 17 and 21, followed by the alkylation and Stille reactions, gave access to the nitrostyrenes 20 and 23, respectively.¹⁵ Having in hand 2-isopropoxystyrenes, we attempted to synthesize the catalysts 6-10. An exchange reaction of the styrene 14 with Grubbs's carbene 1a in the presence of CuCl, used as a phosphine scavenger, followed by routine flash chromatography leads to the formation of the "first-generation" 5-nitro-substituted carbene 6a as an air-stable brown microcrystalline solid (83% yield).

Scheme 3. Synthesis of Catalysts 6-10a a Reagents and conditions: (a) K2CO3, 20 mol % Cs2CO3, iPrI, DMF, 40 C, 1-2 days; 11, 86%; 12, 56%; 13, 71%. (b) (1) Ph3(Me)P+Br-, BuLi, THF, -78 C, 15 min; (2) 11-13, -78 C to room temperature, 48 h; 14, 57%; 15, 67%; 16, 63%. (c) 1b, CuCl, CH2Cl2, 30-40 C, 15-60 min; 6b, 83%; 7b, 83%; 10, 46% or 1a, CuCl, CH2Cl2, 35 C, 55 min; 6a, 83%; 7a, 70%. (d) (1) 24, tC5H11OK, n-hexane, room temperature, 1 h, then 1a, 80 C, 30 min; (2) 14, CuCl, CH2Cl2, 40 C, 1 h, 67-72%. (e) Br2, AcOH, room temperature, 2 h; 92%. (f) HNO3, AcOH, 5 C, 5 min; 39%. (g) K2CO3, 20 mol % Cs2CO3, iPrI, DMF, 40 C, 1 day; 70%. (h) Bu3SnCH=CH2, 5 mol % Pd(Ph3P)4, PhMe, reflux, 6 h; 78%. (i) Br2, AcOH, reflux, 2 h; 55%. (j) K2CO3, 20 mol % Cs2CO3, iPrI, DMF, 35 C, 2 days; 99%. (k) Bu3SnCH=CH2, 3 mol % Pd(Ph3P)4, PhMe, reflux, 4 h; 83%.

The green microcrystalline complex 6b can be easily obtained in a similarly good yield (76-83%) by the reaction of 1b with 14. In the both cases, the reaction can be conveniently monitored by TLC, using cyclohexane/ethyl acetate (4:1) as the eluent.

As synthesis of 6b from the relatively expensive 1b would be somewhat impractical on a larger scale, we adopted a two-step, one-pot process¹¹ using the cheaper "first-generation" carbene 1a as a Ru source. In this procedure, solid 1a was stirred with commercial 4,5-dihydroimidazolium salt 24 in the presence of potassium tert-pentanolate in n-hexane. The in-situ-generated 1b was then treated in the same flask with a solution of styrene 14 and CuCl, providing, after flash chromatography, complex 6b in good yield (67-72%).

The reactions of the styrene 23 with Grubbs's carbenes 1a,b proceeded in a similar manner to give the 4-nitro isomers 7a,b in good yields (70% and 76%, respectively).

The preparation of the next member of this family, complex 8, was more problematic, however. During the reaction between 3-nitro-2-isopropoxystyrene 15 and the Grubbs's complex, we observed by TLC the formation of a new green spot, presumably of the complex 8, that however disappears completely before all the 1b was consumed (1 h, 40 C). All the attempts to capture this unstable product, either by ceasing the reaction at lower conversion or by lowering the temperature, were unsuccessful.¹⁶ A similar behavior was noted in the case of styrene 20, which formed a green complex, presumably 9, that decomposed completely during the isolation/purification step.

We surmised that decreasing the steric bulk near the ortho-chelating iPrO group would lead to a more stable catalyst. The preparation of 10 following the same straightforward route (Scheme 3) leads to the expected complex as a green solid in 46% yield. In a solid form, this compound can be stored in a refrigerator for several days, but it decomposes quickly in solution (see below).

The observed significant instability of 3-substituted 5-nitro complexes 8-10 indicates that combining two modes of activation, steric and electronic, results in great changes in catalyst properties and involves the risk of "over-bursting". This rather disappointing result forced us to abandon the preparation of other members of this series, e.g., a 3,5-dinitro Hoveyda analogue.¹⁷

Relative Reactivity of Various Ruthenium Catalysts. Having a panel of NHC-containing ruthenium complexes (1b-7b, 10) in hand, we decided to study in detail their catalytic activity. For such comparative investigation of relative activity, we chose a model RCM reaction of diene 25, leading to the formation of cyclic product 26 bearing a trisubstituted double bond.^11,12 The results, illustrated in Figure 1, reveal that both catalysts 6b and 7b are significantly more reactive than 2b. The doubly modified complex 10 initializes the reaction; however, it dies after 15 min (Figure 1).

Figure 1 Relative rates of RCM of diene 25 using catalysts 1b, 2b, 6b, 7b, and 10. a1 mol % catalyst, CH2Cl2, room temperature.

As the above reaction proceeds too fast to allow a more accurate comparison of the activity of such potent catalysts, we focused on the more challenging cyclization of 27 at 0 C. According to Blechert and Wakamatsu, 1b gave only ca. 20-30% of cyclized 28 under these conditions.^9b Therefore, this transformation could serve as a calibration point for estimating activity of the highly active catalysts. Figure 2 shows the reaction profile at 0 C for catalysts 2b, 4b, 6b, and 7b. We have found that although the enhancement of reactivity is somewhat lower than that observed for sterically activated 4b, the presence of a NO₂ group leads to catalysts that are dramatically more active than 2b.

Figure 2 Relative rates of RCM of diene 27 using catalysts 1b, 2b, 4b, 6b, and 7b. a1 mol % catalyst, CH2Cl2, 0 C.

Encouraged by these results, we decided to test a broader set of reactions [cross-metathesis (CM), ring-closing metathesis (RCM), and enyne metathesis] in order to obtain a more detailed picture of the application profile of catalysts 6 and 7.

Utility in Catalytic Cross-Metathesis Reactions.¹⁸ We have recently published a novel CM reaction of ,-unsaturated sulfones.¹⁹ Scheme 4 shows a comparative study of the performance of catalysts 1b, 1c, 6b, and 7b in CM of phenyl vinyl sulfone and the highly substituted indole 29. Although CM of this challenging substrate, a "dead-end intermediate" ²⁰ in total synthesis of 1,3,4,5-tetrahydrobenz[c,d]indol-4-amine alkaloids,²¹ is possible with Grubbs's "second-generation" carbene 1b, the highest conversions and lowest catalyst loadings can be achieved in the case of 6b and 7b (Scheme 4). The catalytic CM of selected ,-unsaturated substrates was then examined. The results compiled in Table 1 illustrate the remarkably wide scope of these catalysts. Thus, (i) the CM reactions of methyl acrylate (entries 1 and 12) and methyl vinyl ketone (entry 7) can be efficiently performed at room temperature; (ii) in the case of reactive alkenes, even CM of phenyl vinyl sulfone and acrylonitrile was possible at ambient temperature (entries 2-4, 9) [however, in the case of vinylphosphine oxides²² (entries 5, 11, and 14) and more demanding olefinic partners (e.g., entries 6, 10, and 13), reflux temperature (40 C) was required to achieve good conversions]; (iii) the indole nitrogen and other functionalities do not require protection. Most remarkably, the new catalyst 6b can be used for CM of methacrylonitrile, a transformation which is beyond the scope of the "second-generation" Grubbs's carbene 1b (entry 8).

Scheme 4. Comparison of the Activity of Catalysts 1b, 1c, 6a, and 7b in CM of Phenyl Vinyl Sulfone a Conditions: 5-10 mol % catalyst, 2 equiv of phenyl vinyl sulfone, 40 C, CH2Cl2, 16 h. bIsolated yields after silica gel chromatography.

Recently, we described a novel "homo-metathesis" ²⁴ reaction of vinyl phosphine oxide 45 catalyzed by 6b.²² Interestingly, 1b and 2b are clearly less potent in the formation of 46 (Scheme 5).^25,26 These examples of demanding CM reactions show that 6b and 7b are by all means superior to 1b and 2b.

Scheme 5. Comparison of the Activity of Catalysts 1b and 6a in Homocoupling of (-)-45 25 a Conditions: 5 mol % catalyst, 40 C, CH2Cl2, 16 h. bIsolated yields after silica gel chromatography. cYield determined by 31P NMR.

Utility in the Formation of Tri- and Tetrasubstituted C-C Double Bonds. As illustrated in Table 2, the nitro-substituted complexes 6b and 7b serve as effective catalysts for formation of di- and trisubstituted double bonds. The RCM and enyne metathesis reactions can be performed efficiently even at 0 C (Table 2, entries 1-4). Furthermore, the potential of a nitro catalyst for more challenging metathesis reactions has been proved (entries 5-12). Various degrees of substitution of the double bond are tolerated, and even trisubstituted cyclic olefins can be synthesized in usually good yields (entries 5-7). The CM of terminal alkenes with internal olefins (entry 10) and 2-methyl-2-butene²⁷ (entries 8, 9) proceeds very efficiently. In all reported cases, complex 6b exhibits similar levels of activity as compared with Grubbs's carbene 1b. The catalytic cross-metathesis reactions of 1,1-disubstituted olefins represent, however, a more difficult case for 6b (entries 11-13).

Having established the application profile of the nitro-substituted Hoveyda-type catalysts in the formation of di- and trisubstituted C-C double bonds, we focused our efforts on the most demanding case-the formation of the tetrasubstituted C-C double bonds.²⁹

As can be seen from Table 3, the NO₂-containing complex 6b effected the cyclization of substrates 58, albeit in lower yield (entry 1). The analogous malonate derivative 60 was even more reluctant toward cyclization (Table 3, entry 2).²⁸ Entries 1-3 show that, in general, the Hoveyda-type catalysts are inferior to Grubbs's carbene 1b in the formation of tetrasubstituted C-C double bonds.²⁹

Stability and Recyclability of Nitro-Substitited Ru Complexes. The ruthenium carbenes 6a,b and 7a,b possess very good air, moisture, and thermal stability and can be handled in air and stored for extended periods of time (more than six months at +4 C) without decomposition or diminishing of their activity.³⁰ One of the unique properties of the Hoveyda-Grubbs carbene 2b is that up to 95% of the catalyst can be recovered after the reaction.^2b However, no data were provided until now regarding the recyclability of the more active catalysts: 4b and 6b.^9,12 To answer this question, we attempted to isolate the NO₂ catalyst after CM and RCM reactions. It was found that, in many cases, 6b can be recovered with good to moderate efficiency (70-40%). As an example, in the formation of 47 (99% conversion, Table 2, entry 1), recovered 6b was obtained in 72% yield. In the preparation of 49 (2.5 mol % of 6b, 20 C, 99% conversion, Table 2, entry 4), 40% of the catalyst was isolated after chromatography. However, in the case of CM reaction with acrylate (Table 1, entry 1), no catalyst was recovered. Similarly, prolonged reaction times at higher temperature (Table 3) led to decomposition of the catalyst.³¹

Synthetic Utility of the First-Generation Complexes 6a and 7a. In a second set of experiments, the utility of the first-generation complexes 6a and 7a in the formation of various heterocycles via RCM and enyne reactions was revealed (Table 4). Catalyst loadings lower than 5 mol % were sufficient.

In the course of this investigation, we observed that the use of the catalyst 6b for metathesis of 66 led to the generation of an undesired product 68 (Table 5, entry 1). The same byproduct was formed in reactions promoted by other second-generation Hoveyda-type carbenes (entries 2, 3). A similar lack of selectivity has been reported by Mori for enyne reactions of 1c with enynes having a 1,1-disubstituted alkene and an internal alkyne motif.³² The byproduct formed in reaction of 66 decomposes easily, leading to undefined material, but could be isolated by a quick flash chromatography on silica gel and characterized by ¹H NMR and HRMS. The proposed structure 68 agrees well with a possible reaction mechanism proposed by Mori.³² Interestingly, both of the first-generation complexes 6a and 7a show in this transformation a high level of selectivity, leading only to the formation of 67.

Considerations Regarding the Structure-Activity Relationship of Substituted Hoveyda Catalysts. It has been reported by Hoveyda that the variation from an isopropoxy to a methoxy chelating group has a negative impact on the catalyst performance, since the 2-methoxy analogue 69 (Scheme 5) was significantly less stable and less reactive than 2a.^2a In light of this observation, it is worthwhile to note that the electron-donating group (EDG) substituted carbene 5 with a MeO-chelating group shows not only good catalytic activity but also perfect stability.¹¹ An electron-withdrawing group (EWG) analogue, 70 has been therefore prepared from commercially available 2-methoxy-5-nitrobenzaldehyde via olefination and exchange reaction of the resulting styrene with 1b.¹⁵ However, this complex was difficult to synthesize and purify in good yield (39% of an exchange reaction with 1b), while the catalyst 5, bearing electron-donating substituents, was almost quantitatively prepared.¹¹ Moreover, 70 proved to be a less effective catalyst than its iPr analogue (only 75% conversion after 2 h in a model reaction shown in Figure 1). The difference in properties of 6b and 70 indicates that the nature of the ether chelate is more critical to the stability, as well as the activity, of complexes bearing EWGs than of those containing EDG substituents.

Scheme 6

In the course of our project aimed at the preparation of the immobilized metathesis catalyst, we prepared the bromo analogue 71 of the Hoveyda catalyst 2b.^6b Although the reactivity patterns of complexes 2b and 71 were in general similar, the latter system was visibly less reactive in some model reactions.^19b These results once again show that even a small variation in the benzylidene sphere can result in a change in the activity of the catalyst.

The effect of substitution of the benzylidene fragment on a catalyst's activity has been studied in detail and interpreted by means of ⁺ values by Blechert et al.¹³ In our current investigation, we decided to perform a preliminary ab initio calculation of an electron density distribution, viewed as electrostatic potential (ESP) or Mulliken charges in selected 2-isopropoxystyrenes.³³

This approach should provide more information regarding the relative importance of electron density at either the vinyl fragment (precursor of a benzylidene) or the chelating isopropoxy group. The calculated values of ESP charges in 2-isopropoxy-5-nitrostyrene (14) and 2-isopropoxy-4-nitrostyrene (16) indicate that, in comparison with the unsubstituted 2-isopropoxystyrene 72, the electron density at the iPrO oxygen atom is lowered in both regioisomers, while C-7 carbons show evidently increased ESP charge (Scheme 6).³⁵ The comparison of Mulliken charges³⁴ (ESP not available) in 2-isopropoxy-4-bromostyrene revealed increased electron density at both the iPrO oxygen and the C-7 carbon. Although this approach is an oversimplification of a real situation and provides no information regarding the real catalysts, it is in good agreement with activity profiles and NMR spectra of 2b, 6b, 7b, and 71. Comparison of the 500 MHz ¹H and ¹³C NMR spectra reveals some of the subtle electronic attributes of these systems. As illustrated in Scheme 5, the iPrO methine proton and carbon appear more downfield in both 6b and 7b. This may be attributed to lower electron density at the iPrO center as compared with 2b. Conversely, Ru=CH carbons in 6b and 7b are shifted more upfield.³⁶

Conclusion

The data reported in this paper witness that the Hoveyda-type catalysts can be significantly improved by changing not only the steric but also the electronic situation in the Ru-chelating isopropoxy fragment. This notion has strong implications for catalyst design and application, which will be studied in more detail during our research program. Attempts to combine the two modes of activation of 2, steric and electronic, resulted in severely decreasing the catalyst's stability. This indicates that the effect of structural modifications of complex 2 does not always correspond to those of the related chiral complexes.¹⁷ Although the presence of a NO₂ group leads to catalysts that are dramatically more active than both 1b and 2b, enhancement of reactivity is somewhat lower than that observed for sterically activated 4b. However, taking in account simple preparation, partial recyclability, excellent stability, and high activity, the nitro-substituted Hoveyda catalysts 6 and 7 are very attractive from a practical point of view,^12b,c even if they do not surpass the hindered catalyst 4b in terms of initiation speed.

Equally noteworthy is the fact that different NHC catalysts turned out to be optimal for different applications. Whereas the phosphine-free carbenes are proven to be catalysts of choice for CM of various electron-deficient alkenes, they exhibit lower reactivity toward tetrasubstituted double bonds. This shows that no single catalyst outperforms all others in all possible applications.³⁷

Acknowledgment

Financial support was provided by the State Committee of Scientific Research (Grant No. 4 T09A 136 22). We thank Micha Barbasiewicz for helpful discussions and for critical reading of this manuscript. A.M. thanks the IOC PAS for a pre-doctoral fellowship. We are grateful to Mr. C. Samojowicz for technical assistance. This article is dedicated to Professor Mieczysaw Mkosza on the occasion of his 70th birthday.