Nitro-substituted Hoveyda-Grubbs ruthenium carbenes: Enhancement of catalyst activity through electronic activation

Article abstract of DOI:10.1021/ja048794v

The design, synthesis, stability, and catalytic activity of nitro-substituted Hoveyda-Grubbs metathesis catalysts are described. The highly active and stable meta- and para-substituted complexes are attractive from a practical point of view. These catalys

Full text of DOI:10.1021/ja048794v

Published on Web 07/13/2004
Nitro-Substituted Hoveyda-Grubbs Ruthenium Carbenes:
Enhancement of Catalyst Activity through Electronic
Activation
Anna Michrowska,† Robert Bujok,† Syuzanna Harutyunyan,† Volodymyr Sashuk,†
Grigory Dolgonos,‡ and Karol Grela*,†
Contribution from the Institutes of Organic Chemistry and Physical Chemistry,
Polish Academy of Sciences, 01-224 Warsaw, Poland
Received March 2, 2004; E-mail: grela@icho.edu.pl
Abstract: The design, synthesis, stability, and catalytic activity of nitro-substituted Hoveyda-Grubbs
metathesis catalysts are described. The highly active and stable meta- and para-substituted complexes
are attractive from a practical point of view. These catalysts operate in very mild conditions and can be
successfully applied in various types of metathesis [ring-closing metathesis, cross-metathesis (CM), and
enyne metathesis]. Although the presence of a NO2 group leads to catalysts that are dramatically more
active than both the second-generation Grubbs’s catalyst and the phosphine-free Hoveyda’s carbene,
enhancement of reactivity is somewhat lower than that observed for a sterically activated Hoveyda-Grubbs
catalyst. Attempts to combine two modes of activation, steric and electronic, result in severely decreasing
a catalyst’s stability. The present findings illustrate that different Ru catalysts turned out to be optimal for
different applications. Whereas phosphine-free carbenes are catalysts of choice for CM of various electron-
deficient substrates, they exhibit lower reactivity in the formation of tetrasubstituted double bonds. This
demonstrates that no single catalyst outperforms all others in all possible applications.
Introduction
ease of storage, and handling and the possibility of catalyst reuse
and immobilization6 constitute additional advantages of this
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 de-
velopment of efficient and selective catalysts 1a-c has been
the key to the widespread application of olefin metathesis in
organic synthesis.1
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 f Ru electron donation).8 Blechert and Waka-
matsu have shown recently that replacement of the isopropoxy-
benzylidene “ligand” in 2 by BINOL- or biphenyl-based
benzylidene results in a large improvement in catalyst activity,
assfor examplescomplex 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 frag-
Although the second-generation Grubbs’s ruthenium catalyst
1b possesses in general a very good application profile, com-
bining 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 reac-
tivity levels toward electron-deficient substrates, such as acrylo-
nitrile,4 fluorinated olefins,5 and others.3 Excellent air-stability,
(4) (a) Randl, S.; Gessler, S.; Wakamatsu, H.; Blechert, S. Synlett 2001, 430-
432. For activation of Grubbs’s carbene 2b toward acrylonitrile, via either
structural modifications or addition of CuCl, see: (b) Love, J. A.; Morgan,
J. P.; Trnka, T. M.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002, 41, 4035-
4037. (c) Rivard, M.; Blechert, S. Eur. J. Org. Chem. 2003, 2225-2228.
(5) Imhof, S.; Randl, S.; Blechert, S. Chem. Commun. 2001, 1692-1693.
(6) For syntheses of supported variants of 2, see inter alia ref 2b and (a)
Kingsbury, J. S.; Garber, S. B.; Giftos, J. M.; Gray, B. L.; Okamoto, M.
M.; Farrer, R. A.; Fourkas, J. T.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2001, 40, 4251-4255. (b) Grela, K.; Tryznowski, M.; Bieniek, M.
Tetrahedron Lett. 2002, 43, 9055-9059. (c) Connon, S. J.; Dunne, A. M.;
Blechert, S. Angew. Chem., Int. Ed. 2002, 41, 3835-3838. (d) Dowden,
J.; Savovic, J. Chem. Commun. 2001, 37-38. (e) Yao, Q. Angew. Chem.,
Int. Ed. 2000, 39, 3896-3898. (f) Yao Q.; Zhang, Y. Angew. Chem., Int.
Ed. 2003, 42, 3395-3398. (g) Connon, S. J.; Blechert, S. Bioorg. Med.
Chem. Lett. 2002, 12, 1873-1876. (h) Yao, Q.; Zhang, Y. J. Am. Chem.
Soc. 2004, 12, 74-75. (i) Yao, Q.; Motta, A. R. Tetrahedron Lett. 2004,
45, 2447-2451.
† Institute of Organic Chemistry
‡ Institute of Physical Chemistry
(1) Pertinent reviews: (a) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2003, 42, 4592-4633. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18-29. (c) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39,
3012-3043. (d) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-
4450. (e) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997,
36, 2037-2056. (f) Dragutan, V.; Dragutan, I.; Balaban, A. T. Platinum
Metals ReV. 2001, 45, 155-163.
(2) (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.
(3) For a short review on these catalysts, see: Hoveyda, A. H.; Gillingham,
D. G.; Van Veldhuizen, J. J.; Kataoka, O.; Garber, S. B.; Kingsbury, J. S.;
Harrity, J. P. A. Org. Biomol. Chem. 2004, 2, 1-16.
(7) Catalysts 2 are commercially available from Aldrich Chemical Co.
(8) For a comparison of relative initiation rates of 1b and 2b, see refs 9a,b,
11, and 12.
9
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J. AM. CHEM. SOC. 2004, 126, 9318-9325
10.1021/ja048794v CCC: $27.50 © 2004 American Chemical Society

Nitro-Substituted Hoveyda−Grubbs Ruthenium Carbenes
A R T I C L E S
Scheme 1. Family of Ruthenium Catalysts for Alkene Metathesisa
Scheme 2
a Cy ) cyclohexyl; Mes ) 2,4,6-trimethylphenyl.
ment. Catalyst 5, which is very stable and easy to prepare from
inexpensive R-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 f Ru chelation and facilitate initiation
of the catalytic cycle.12-14 Herein we report a more compre-
hensive 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).
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 bulk9b close to the chelating
isopropoxy fragment could result in an even higher increase of
catalytic activity (Scheme 2).
Results and Discussion
Preparation. As illustrated in Scheme 3, we used com-
mercially 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-iso-
propoxystyrenes, 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).
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%).
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
(9) (a) Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. 2002, 41, 794-
796. (b) Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. 2002, 41,
2403-2405. (c) For an improved synthesis of 4b and reactivity studies,
see: Dunne, A. M.; Mix, S.; Blechert, S. Tetrahedron Lett. 2003, 44, 2733-
2736.
(10) Extensive studies described in ref 9b,c suggest that a steric bulk adjacent
to the chelating isopropoxy moiety of 3b and 4b is the crucial factor
securing the unusually high activity of these complexes.
(11) (a) Grela, K.; Kim, M. Eur. J. Org. Chem. 2003, 963-966. (b) For a unique
activity of a catalyst derived from 5 in living polymerization of diynes,
see: Krause, J. O.; Zarka, M. T.; Anders, U.; Weberskirch, R.; Nuyken,
O.; Buchmeiser, M. R. Angew. Chem., Int. Ed. 2003, 42, 5965-5969.
(12) (a) Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem., Int. Ed.
2002, 41, 4038-4040. For applications of 6b in target-oriented synthesis,
see the following. (b) (-)-Securinine: Honda, T.; Namiki, H.; Kaneda,
K.; Mizutani, H. Org. Lett. 2004, 6, 87-89. (c) An artificial photosynthesis
model: Ostrowski, S.; Mikus, A. Mol. DiVers. 2003, 6, 315-321. (d)
Harutyunyan, S.; Michrowska, A.; Grela, K. In Catalysts for Fine Chemical
Synthesis; Roberts, S., Ed; Wiley-Interscience: New York, 2004; Vol. 3,
in press.
(13) (a) After our report on 6b, another study on the effects of EWG and EDG
substituents in the benzylidene part of 2 on the rate of metathesis was
published: Zaja, M.; Connon, S. J.; Dunne, A. M.; Rivard, M.; Buschmann,
N.; Jiricek, J.; Blechert, S.Tetrahedron 2003, 59, 6545-6558. (b) For an
application of a CN-substituted Hoveyda-Grubbs catalyst, see: Connon,
S. J.; Rivard, M.; Zaja, M.; Blechert, S. AdV. Synth. Catal. 2003, 345, 572-
575.
(14) (a) In the case of Hoveyda-Grubbs complexes, initiation requires dis-
sociation of the aryl ether ligand as well as a metathesis step. The slower
rate of initiation of 2a,b is likely due to the less facile dissociation of the
bidentate ligand from the metal center (ref 2). The suppression of oxygen
reassociation to the Ru center caused by a para-NO2 group and the increased
electron deficiency at the initiating carbene species should make 6b more
active in olefin metathesis. (b) For other types of Ru metathesis catalysts
bearing a NO2 group, see: De Clercq, B.; Verpoort, F. AdV. Synth. Catal.
2002, 344, 639-648. (c) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am.
Chem. Soc. 1996, 118, 100-110.
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).
(15) See the Supporting Information for experimental details.
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A R T I C L E S
Michrowska et al.
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) Bu3SnCHdCH2, 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) Bu3SnCHdCH2, 3 mol % Pd(Ph3P)4, PhMe, reflux, 4 h; 83%.
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 acti-
Figure 1. Relative rates of RCM of diene 25 using catalysts 1b, 2b, 6b,
7b, and 10. 1 mol % catalyst, CH2Cl2, room temperature.
a
vation, 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).
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,
(16) The instability of 8 can be explained in view of the increased steric demand
of the nitro group, which tends to be in the same plane as the benzene
ring. According to ab initio calculation of the minimum-energy conforma-
tion of styrene 15, the NO2 group is twisted 22.1° off-plane. See the
Supporting Information and ref 33 for computational details.
(17) Recently, the concept of steric and electronic activation has been utilized
by Hoveyda et al. in a preparation of chiral ruthenium complexes for
asymmetric metathesis. The results show that the steric hindrance exhibits
a more pronounced effect on a catalyst’s activity. For example, while the
introduction of a NO2 group led to a complex that is 3 times more potent
than an unmodified catalyst, a sterically hindered one acts more than 100
times faster in the same model reaction. However, both modes of activation
can be successfully combined in this case, as the doubly (sterically and
electronically) modified chiral complex possessed the highest level of
potency among those studied. Van Veldhuizen, J. J.; Gillingham, D. G.;
Garber, S. B.; Kataoka, O.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125,
12502-12508.
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Nitro-Substituted Hoveyda−Grubbs Ruthenium Carbenes
A R T I C L E S
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
b
°C, CH2Cl2, 16 h. Isolated yields after silica gel chromatography.
ature; (ii) in the case of reactive alkenes, even CM of phenyl
vinyl sulfone and acrylonitrile was possible at ambient temper-
ature (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).
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.
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-
Figure 2. Relative rates of RCM of diene 27 using catalysts 1b, 2b, 4b,
6b, and 7b. 1 mol % catalyst, CH2Cl2, 0 °C.
a
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.
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 R,â-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 R,â-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 temper-
(22) Demchuk, O. M.; Pietrusiewicz, K. M.; Michrowska, A.; Grela, K. Org.
Lett. 2003, 5, 3217-3220.
(23) Optical purity was calculated from the 31P and 1H NMR spectra registered
in the presence of (S)-N-[1-(1-naphthyl)ethyl]-3,5-dinitrobenzamide (Kagan
shift reagent). Cf. ref. 22 and (a) Pakulski, Z.; Demchuk, O. M.; Kwiatosz,
R.; Osin˜ski, P. W.; Wierczyn˜ska, W.; Pietrusiewicz, K. M. Tetrahedron:
Asymmetry 2003, 14, 1459-1462. (b) Deshmukh, M.; Dunach, E.; Juge,
S.; Kagan, H. B. Tetrahedron Lett. 1984, 25, 3467-3470.
(18) For reviews on catalytic cross-metathesis, see: (a) Vernall, A. J.; Abell,
A. D. Aldrichimica Acta 2003, 36, 93-105. (b) Blechert, S.; Connon, S. J.
Angew. Chem., Int. Ed. 2003, 42, 1900-1923. (c) Blackwell, H. E.;
O’Leary, D. J.; Chatterjee, A. K.; Washenfelder, R. A.; Bussmann, D. A.;
Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58-71. (d) For a short review
on applications to commercial products, see: Pederson, R. L.; Fellows, I.
M.; Ung, T. A.; Ishihara, H.; Hajela, S. P. AdV. Synth. Catal. 2002, 344,
728-735. (e) For a general model for selectivity in olefin CM, see:
Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem.
Soc. 2003, 125, 11360-11370.
(24) The examples of metathesis between two electron-deficient olefins are rare,
and good yields have been reported only for homodimerization of acrylates
and for cross-metathesis of R,â-unsaturated substrates with styrenes. See:
(a) Choi, T.-L.; Lee, C. W.; Chatterjee, A. K.; Grubbs, R. H. J. Am. Chem.
Soc. 2001, 123, 10417-10418. (b) Chatterjee, A. K.; Toste, F. D.; Choi,
T.-L.; Grubbs, R. H. AdV. Synth. Catal. 2002, 344, 634-637.
(25) Michrowska, A.; Szmigielska, A.; Demchuk, O. M.; Butenscho¨n, H.;
Pietrusiewicz, K. M.; Grela, K. Unpublished.
(26) The similar lack of activity of 1b in homocoupling of vinylphosphine oxides
has been reported independently: Bisaro, F.; Gouverneur, V. Tetrahedron
Lett. 2003, 44, 7133-7135.
(27) CM of terminal olefins and 2-methyl-2-butene, reported by Grubbs et al.,
constitutes a very elegant method of an allyl-to-prenyl conversion:
Chatterjee, A. K.; Sanders, D. P.; Grubbs, R. H. Org. Lett. 2002, 4, 1939-
1942.
(19) (a) Grela, K.; Bieniek, M. Tetrahedron Lett. 2001, 42, 6425-6428. (b)
Grela, K.; Michrowska, A.; Bieniek, M.; Kim, M.; Klajn, R. Tetrahedron
2003, 59, 4525-4531. (c) For an application of this transformation in the
enantioselective synthesis of furanone natural products, see: Evans, P.;
Leffray, M. Tetrahedron 2003, 59, 7973-7981.
(20) Sierra, M. A.; de la Torre, M. C.Angew. Chem., Int. Ed. 2000, 39, 1538-
1559.
(21) Ma¸kosza, M.; Stalewski, J.; Wojciechowski, K.; Danikiewicz, W. Tetra-
hedron 1997, 53, 193-214.
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Table 1. CM of R,â-Substrates Catalyzed by 6b, 7b, and Other Ruthenium Carbenesa
a Conditions: 1-5 mol % catalyst, 25-40 °C, CH2Cl2 or 80 °C, toluene. b Isolated yields after silica gel chromatography unless stated otherwise. c Reaction
with 2 equiv of methyl acrylate. d Yield determined by GC. e Reaction with 2 equiv of acrylonitrile. f (E):(Z) ) 1:3, ref 4. g Reaction with 2 equiv of phenyl
vinyl sulfone. h Reaction with 2 equiv of diphenyl vinyl phosphine oxide. i Reaction with 2 equiv of methyl vinyl ketone. j Reaction with 4 equiv of
methacrylonitrile. k References 22 and 23.
Scheme 5. Comparison of the Activity of Catalysts 1b and 6a in
As can be seen from Table 3, the NO2-containing complex
6b effected the cyclization of substrates 58, albeit in lower yield
Homocoupling of (-)-45 25
(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 Com-
plexes. The ruthenium carbenes 6a,b and 7a,b possess very good
(28) Significantly higher yields in the cyclisation of dienes shown in Table 3
b
have been reported in the literature. (a) 61, 31% (5 mol % of 1b; 24 h in
refluxing DCM; NMR yield): Scholl, M.; Ding, S.; Lee, C. W.; Grubbs,
R. H. Org. Lett. 1999, 1, 953-956. (b) 59, 95% (5 mol % of 1c; toluene,
80 °C, 24 h; isolated yield); 61, 47% (5 mol % of 1c; toluene, 80 °C, 24
h; GC yield); 62, 75% (5 mol % of 1c; toluene, 80 °C, 18 h; isolated yield);
cf.: Fu¨rstner, A.; Ackermann, L.; Gabor, B.; Goddard, R.; Lehmann, C.
W.; Mynott, R.; Stelzer, F.; Thiel, O. R. Chem. Eur. J. 2001, 7, 3236-
3253.
a Conditions: 5 mol % catalyst, 40 °C, CH2Cl2, 16 h. Isolated yields
after silica gel chromatography. Yield determined by 31P NMR.
c
metathesis reactions of 1,1-disubstituted olefins represent, how-
ever, 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 casesthe formation of the tetrasubstituted C-C
double bonds.29
(29) (a) There are no separate reports devoted to applications of the Hoveyda-
Grubbs catalysts for the preparation of tetrasubstituted C-C double bonds.
However, Hoveyda et al. have noted that tetrasubstituted olefins were
obtained less efficiently through catalytic RCM promoted by 2b (ref 2).
For a possible explanation of the lower level of efficiency observed with
2b, see ref 3. (b) For some examples of the formation of tetrasubstituted
olefins with Hoveyda-type catalysts, see also ref 6b,h,i.
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Nitro-Substituted Hoveyda−Grubbs Ruthenium Carbenes
A R T I C L E S
Table 2. Formation of Di- and Trisubstituted Double Bonds Promoted by 6b, 7b, and Other Catalystsa
a Conditions: 1-5 mol % catalyst, 0-40 °C, CH2Cl2 or 80 °C, toluene. b Isolated yields after silica gel chromatography unless stated otherwise. c Reference
28b. d Reference 9b e Yield determined by GC. f Reaction with neat 2-methyl-2-butene. Reference 27. g Reaction with 2 equiv of (Z)-4-(acetyloxy)-2-
butenyl acetate. h Yield based on recovered starting material. i Reaction with 2 equiv of allyl(trimethyl)silane.
Table 3. Formation of Tetrasubstituted Double Bonds Promoted
at +4 °C) without decomposition or diminishing of their
by 1b, 2b, 4b, 6b, and 7ba
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 tem-
perature (Table 3) led to decomposition of the catalyst.31
(30) The complex 6b is stable up to 110 °C and efficiently promotes metathesis
at 80 °C in toluene. Grela, K.; Bieniek, M. Unpublished. For the stability
of 2b and 4b, see refs 2 and 9, respectively.
(31) In general, the recyclability of 6b is handicapped as compared with that of
2b, and typically 6b can be recovered after metathesis reaction only with
moderate efficiency. See the Supporting Information for the recovery
experiments.
a Conditions: 5 mol % catalyst, 40 °C, CH2Cl2. b Yields determined by
GC.
air, moisture, and thermal stability and can be handled in air
and stored for extended periods of time (more than six months
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A R T I C L E S
Michrowska et al.
Table 4. Metathesis Reactions Promoted by the First-Generation
Catalysts 6a and 7aa
Scheme 6
a Conditions: 1-2.5 mol % catalyst, 25 °C, CH2Cl2. b Isolated yields
after silica gel chromatography. c Determined by GC.
Table 5. Investigation of the First- and Second-Generation
Catalysts in Enyne Metathesis of 66
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.
In the course of our project aimed at the preparation of the
immobilized metathesis catalyst, we prepared the bromo ana-
logue 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.
a Conditions: 1-2.5 mol % catalyst, CH2Cl2, 24 h, 25 °C. b Isolated
yields after silica gel chromatography. In parentheses are the GC yields.
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.
The effect of substitution of the benzylidene fragment on a
catalyst’s activity has been studied in detail and interpreted by
means of σ+ values by Blechert et al.13 In our current in-
vestigation, we decided to perform a preliminary ab initio cal-
culation of an electron density distribution, viewed as electro-
static potential (ESP) or Mulliken charges in selected 2-isopro-
poxystyrenes.33
Considerations Regarding the Structure-Activity Rela-
tionship 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
This approach should provide more information regarding
the relative importance of electron density at either the vinyl
(33) All the calculations were performed using Gaussian 98 (Gaussian 98,
Revision A.11.4; Gaussian, Inc.: Pittsburgh, PA, 2002) on an IRIX64/
Linux workstation. The structures of 2-isopropoxystyrenes were optimized
using B3LYP with the 6-31G** basis set. Only real values of the analytical
harmonic vibrational frequencies confirmed that the geometries under study
correspond to the minimum-energy structures.
(32) (a) Kitamura, T.; Sato, Y.; Mori, M. AdV. Synth. Catal. 2002, 344, 678-
693. (b) Kitamura, T.; Sato, Y.; Mori, M. Chem. Commun. 2001, 1258-
1259.
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Nitro-Substituted Hoveyda−Grubbs Ruthenium Carbenes
A R T I C L E S
fragment (precursor of a benzylidene) or the chelating isopro-
poxy group. The calculated values of ESP charges in 2-isopro-
poxy-5-nitrostyrene (14) and 2-isopropoxy-4-nitrostyrene (16)
indicate that, in comparison with the unsubstituted 2-isopro-
poxystyrene 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
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.
1
of the 500 MHz H and 13C NMR spectra reveals some of the
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 applica-
tions.37
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, RudCH carbons in 6b and 7b are shifted more
upfield.36
Conclusion
Acknowledgment. Financial support was provided by the
State Committee of Scientific Research (Grant No. 4 T09A 136
22). We thank Michał 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.
Samojłowicz for technical assistance. This article is dedicated
to Professor Mieczysław Ma¸kosza on the occasion of his 70th
birthday.
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 implica-
tions for catalyst design and application, which will be studied
(34) Mulliken, R. S. J. Chem. Phys. 1955, 23, 1833.
(35) For a full set of ESP/Mulliken charges, see the Supporting Information.
(36) Similar changes in chemical shifts have been observed for another member
of this series, compound 73: RudCH, 16.34 and 289.8; iPrO methine
proton, 5.01 ppm, and carbon, 78.9 ppm. Arlt, D.; Bieniek, M.; Michrowska,
A.; Bujok, R.; Grela K. Unpublished results.
Supporting Information Available: Full experimental details,
compilation of the instrumentation used, electron density maps
and visualizations, and copies of the NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
JA048794V
(37) For screening of the catalytic performance of catalysts 1b, 2b, 4b, and 6b
in the synthesis of cyclooctenes, see: Sibi, M. P.; Aasmul, M.; Hasegawa,
H.; Subramanian, T. Org. Lett. 2003, 5, 2883-2886.
9
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