Impact of NHC ligand conformation and solvent concentration on the ruthenium-catalyzed ring-closing metathesis reaction

Article abstract of DOI:10.1021/ja903554v

(Figure Presented) Two saturated N-heterocyclic carbene ligands with substituted naphthyl side chains were used for the preparation of Blechert-type ruthenium metathesis precatalysts. The resulting conformers of the complexes were separated and unambiguou

Full text of DOI:10.1021/ja903554v

Published on Web 06/17/2009
Impact of NHC Ligand Conformation and Solvent Concentration on the
Ruthenium-Catalyzed Ring-Closing Metathesis Reaction
Michele Gatti, Ludovic Vieille-Petit, Xinjun Luan, Ronaldo Mariz, Emma Drinkel, Anthony Linden, and
Reto Dorta*
Organic Chemistry Institute, UniVersity of Zurich (UZH), Winterthurerstrasse 190, CH-8057, Zurich, Switzerland
Received May 9, 2009; E-mail: dorta@oci.uzh.ch
Ring-closing metathesis (RCM) reactions promoted by transition
metal catalysts have gained enormous importance in synthetic
organic chemistry.1 Especially valuable was the introduction of
ruthenium-based N-heterocyclic carbene complexes such as Grubbs’
II (GII) a decade ago.1 Since then, major research efforts have
been directed toward optimizing the ligand sphere around the
ruthenium center and have led, inter alia, to derivatives shown in
eq 1.2 Overall though, activities of these catalysts in RCM, while
sufficient for laboratory-scale applications, are still relatively low
for applications in larger-scale reactions.
Figure 1. Ball-and-stick drawings of anti-3 (left) and anti-4 (right).
RCM activities (27 °C, 0.1 M substrate/CD2Cl2) of complexes
anti-3, syn-3, and anti-4 were then benchmarked against Blechert’s
SIMes-derived catalyst (BleII) using a series of substrates (5-15,
Figure 2) and following their conversion by 1H NMR spectroscopy.
Selected kinetic data are shown in Figure 2 (see the Supporting
Information for more details). As anticipated based on our earlier
studies on GII derivatives, the modification of the NHC structure
has a beneficial effect on the reactivity profile and the following
overall order of activity can be deduced: anti-3 g anti-4 > syn-3 >
BleII. Somewhat surprising is the fact that differences in activity
favoring (2,7)-SIPrNap and (2)-SICyNap over SIMes increase with
bulkier substrates that give tri- and tetrasubstituted cyclic olefins
or with dienes that produce six-membered cycloolefins.7 Here, both
anti-3 and anti-4 clearly outperform syn-3 and in particular BleII,
and the overall reactivity profile puts them among the most active
RCM catalysts known.
Our entry into this fascinating field of research began via the
identification of saturated NHCs that feature substituted naphthyl
side chains.3 The ligands are present as a mixture of anti and syn
conformers, and preliminary data with two of these NHCs, (2,7)-
SIPrNap and (2)-SICyNap, outlined their high catalytic activity in
the RCM of GII type precatalysts (used as isomeric mixtures).3c
The substitution pattern on the naphthyl side chains confers a high
degree of conformational stability,3a,4 and we were therefore
intrigued by the prospect of metathesis-active NHC-ruthenium
complexes that are only distinguished by the relative orientation
of their side chains.5
While the higher reactivity of the new catalysts as well as the
clear differences between anti-3 and syn-3 looked very interesting,
we were puzzled by the fact that the BleII catalyst seemed to
perform better than originally reported by Blechert et al.2b A closer
inspection of their report shows that the reaction conditions used,
except for substrate concentration (and catalyst loading), were
identical. This prompted us to examine the dependence of reaction
concentration on RCM activity. To do so, we chose the overall
most active precatalyst (anti-3, 0.1 mol %) and moderately bulky
substrate 7. Figure 2 (below right) shows that reaction rates indeed
increase dramatically with increasing substrate-to-solvent concentra-
tions. Using Blechert’s dilution (0.01 M substrate/CD2Cl2) or a 0.04
M concentration does not lead to full conversion of 7, while a high
concentration (0.8 M) ensured complete conversion after only 21
min. More significantly, a reaction run in an open vessel without
any solvent gave quantitative yields of the product within 2 min,
without generating any byproducts that arise from ADMET.8,9
As a result, neat reactions with other substrates at lower catalyst
loadings were performed with anti-3 (Table 1). In some cases,
namely for the tosylamide-derived substrates, the products were
solids at room temperature and impeded simple, neat reaction runs.
Here, a concentrated hexane solution of anti-3 was added to the
neat substrates giving pure solid products with almost the same
Scheme 1. Preparation and Separation of Catalysts 3 and 4
To enhance the possibility of separating such complexes and at
the same time ensure high catalytic activity, we decided to prepare
phosphine-free ruthenium precatalysts that are analogues to Blech-
ert’s catalyst (BleII).2b Complex 3 was prepared from an anti/syn
mixture (ca. 1:1) of 1 by metathesis with o-isopropoxy-m-
phenylstyrene (Scheme 1). Careful chromatographic workup of the
isomeric mixture led to the isolation of the two complexes anti-3
(first compound eluted) and syn-3 in 63% overall yield. When the
same reaction was performed with an anti/syn (4:1) mixture of 2,
only the first isomer, namely anti-4, was isolated from the column
(62% yield).6 The assignment of the respective isomers was verified
through X-ray structural studies of complexes anti-3 and anti-4
(Figure 1).
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9498 J. AM. CHEM. SOC. 2009, 131, 9498–9499
10.1021/ja903554v CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
In conclusion, we have identified ruthenium metathesis catalysts
that show improved reactivity profiles for the RCM and where clear
differences exist between the respective conformers of the NHC
ligand. While testing these new catalysts, we discovered that
substantially higher reaction rates could be obtained when more
concentrated substrate/solvent mixtures were employed. This
ultimately led to the RCM forming five- and six-membered rings
of a variety of substrates with catalyst loadings of just 50-250
ppm of anti-3. This simple and practical way for improving the
reactivity and the lifetime of anti-3 seems to be applicable to other
ruthenium metathesis catalysts and should extend their usefulness
in chemical synthesis. The intriguing reactivity differences between
anti-3 and syn-3 are now the subject of a mechanistic study that
will be extended to metathesis reactions using chiral derivatives of
the ligands described here.11
Acknowledgment. We thank the Alfred Werner Foundation
(R.D.), the Swiss National Foundation (R.M.), the Roche Research
Foundation (E.D.), and UZH (M.G., L.V.P., X.L.) for support.
Supporting Information Available: Experimental procedures,
kinetic data, and CIFs for anti-3 and anti-4. This material is available
free of charge via the Internet at http://pubs.acs.org.
Figure 2. Substrates (above, catatyst loadings for 5-8, 10-14; 0.1 mol
%, for 15; 0.2 mol %; for 9; 2 mol %), kinetic data for RCM of 7, 9, and
11, and concentration dependence for conversion of 7 with anti-3 (below).
References
(1) (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (b) Grubbs,
R. H. Handbook of Metathesis; Wiley-VCH: Weinheim, Germany, 2003.
(2) HovII: (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168. BleII: (b) Wakamatsu, H.; Blechert,
S. Angew. Chem., Int. Ed. 2002, 41, 2403 GreII: (c) Grela, K.; Harutyunyan,
S.; Michrowska, A. Angew. Chem., Int. Ed. 2002, 41, 4038 LAGII: Bieniek,
M.; Bujok, R.; Cabaj, M.; Lugan, N.; Lavigne, G.; Arlt, D.; Grela, K. J. Am.
Chem. Soc. 2006, 128, 13652.
(3) (a) Luan, X.; Mariz, R.; Gatti, M.; Costabile, C.; Poater, A.; Cavallo, L.;
Linden, A.; Dorta, R. J. Am. Chem. Soc. 2008, 130, 6848. (b) Vieille-
Petit, L.; Luan, X.; Mariz, R.; Blumentritt, S.; Linden, A.; Dorta, R. Eur.
J. Inorg. Chem. 2009, 1861. (c) Vieille-Petit, L.; Luan, X.; Gatti, M.;
Blumentritt, S.; Linden, S.; Clavier, H.; Nolan, S. P.; Dorta, R. Chem.
Commun. 2009, 3783.
efficiency as that of the neat reactions. Overall, catalyst loadings
could be significantly lowered compared to the runs performed in
solution. Although not optimized, between 50 and 250 ppm of
precatalyst anti-3 at room temperature suffice for virtually complete
conversion to give ring-closed disubstituted and trisubstituted five-
and six-membered rings. Generation of ethylene gas is not necessary
for the reaction to proceed (entries 13-15). In the case of the
representative enyne substrate 10, a concentrated CH2Cl2 solution
already ensures unprecedented levels of activity (entries 9,10). Also
notable is the very low catalyst loading (0.2 mol %) needed to obtain
the tetrasubstituted olefin from 9 (entry 8). This product is normally
only produced with heating and substantially higher catalyst
loadings. Turnover numbers reaching 20 000 (entries 2,10,12) and
turnover frequencies of 240 000 per hour (entries 1,11,13) for
complete conversion certainly approach values needed for larger-
scale industrial applications of the RCM reaction.10
(4) Similar NHCs with unsymmetrical phenyl side chains are fluxional, see:
Stewart, I. C.; Benitez, D.; O’Leary, D. J.; Tkatchouk, E.; Day, M. W.;
Goddard, W. A.; Grubbs, R. H. J. Am. Chem. Soc. 2009, 131, 1931.
(5) Such systems might show differences in catalytic performance and could
serve as ideal models for studying some of the mechanistically relevant
and still disputed steps of metathesis reactions; see: (a) Romero, P. E.;
Piers, W. E. J. Am. Chem. Soc. 2005, 127, 5032. (b) Wenzel, A. G.; Grubbs,
R. H. J. Am. Chem. Soc. 2006, 128, 16048. (c) Romero, P. E.; Piers, W. E.
J. Am. Chem. Soc. 2007, 129, 1698. (d) Van der Eide, E. F.; Romero, P. E.;
Piers, W. E. J. Am. Chem. Soc. 2008, 130, 4485.
(6) See the Supporting Information for details.
Table 1. RCM (25°C) with anti-3 at Low Catalyst Loadings
(7) The results seem counterintuitive given the overall higher steric bulk of
(2,7)-SIPrNap and (2)-SICyNap compared to SIMes (ref 3a).We believe
that this is due to the fact that one of the sides on the naphthyl moieties is
more open than in SIMes and, as a consequence, bulky substrates can
approach the metal center more easily.
entry
olefin
conditions
anti-3 (ppm)
t (min)
yield (%)a
1
5
5
6
6
7
8
8
9
10
10
11
11
12
13
14
15
neat
neat
250
50
1
120
5
12
30
9
18
480
4
30
1
120
1
5
480
480
99 (97)
97
98 (96)
97
98 (97)
99
97
97
99
99
99
2b
3c
(8) To our knowledge, this is the first study relating reactivity to reaction
concentration since productive RCM was introduced. Early studies on
substrates such as 5 with less selective/active Schrock’s and Grubbs’ I
catalysts showed that productive RCM needed dilutions of at least 0.1 M;
see: (a) Forbes, M. D. E.; Patton, J. T.; Myers, T. L.; Maynard, H. D.;
Smith, D. W.; Schulz, G. R.; Wagener, K. B. J. Am. Chem. Soc. 1992,
114, 10978. (b) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62,
7310. For more recent relevant reports, see: (c) Dinger, M. B.; Mol, J. C.
AdV. Synth. Catal. 2002, 344, 671. (d) Dolman, S. J.; Sattely, E. S.;
Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 2002, 124, 6991. (e)
Maifeld, S. V.; Miller, R. L.; Lee, D. J. Am. Chem. Soc. 2004, 126, 12228.
(9) For insightful recent studies on solvent concentration in macrocyclic RCM:
(a) Conrad, J. C.; Eelman, M. D.; Silva, J. A. D.; Monfette, S.; Parnas, H.;
Snelgrove, J. L.; Fogg, D. E. J. Am. Chem. Soc. 2007, 129, 1024. (b) Shu,
C.; Zeng, X.; Hao, M.-H.; Wei, X.; Yee, N. K.; Busacca, C. A.; Han, Z.;
Farina, V.; Senanayake, C. H. Org. Lett. 2008, 10, 1303.
(10) Grela and more recently Grubbs showed that high TONs can be achieved
when heating 5 in toluene with HovII. However, already 7 gives much
poorer results: (a) Bieniek, M.; Michrowska, A.; Usanov, D. L.; Grela, K.
Chem.sEur. J. 2008, 14, 806. (b) Kuhn, K. M.; Bourg, J.-P.; Chung, C. K.;
Virgil, S. C.; Grubbs, R. H. J. Am. Chem. Soc. 2009, 131, 5313.
(11) Luan, X.; Mariz, R.; Robert, C.; Gatti, M.; Blumentritt, S.; Linden, A.;
Dorta, R. Org. Lett. 2008, 10, 5569.
0.5 M Hex
0.5 M Hex
neat
0.5 M Hex
0.5 M Hex
0.5 M Hex
0.5 M DCM
0.5 M DCM
neat
neat
neat
0.5 M Hex
neat
neat
250
100
250
250
100
2000
100
50
250
50
250
250
250
250
4c
5
6c
7c
8c
9c
10c
11
12b
13
14c
15
16
98
99
99
96
97
a Yields based on NMR analysis. Selected isolated yields in brackets.
b Runs with GII did not go to completion under these conditions but
showed appreciable amounts of product [after 2 h: 72% (5) and 58%
(11), after 24 h: 87% (5) and 72% (11)](ref 6). c DCM ) CH2Cl2, Hex
) n-hexane.
JA903554V
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J. AM. CHEM. SOC. VOL. 131, NO. 27, 2009 9499