Highly active chiral ruthenium-based metathesis catalysts through a monosubstitution in the N-heterocyclic carbene

Article abstract of DOI:10.1002/anie.201000940

(Chemical Equotion Present) Single (substitution) is better: New chiral ruthenium metathesis (pre)catalysts with a monosubstituted carbon atom in the N-heterocyclic carbene ligand are highly stable in solution, initiate easily, show very high enantioselectivity and excellent E selectivity in asymmetric ring-opening cross-metathesis (see scheme).

Full text of DOI:10.1002/anie.201000940

Communications
DOI: 10.1002/anie.201000940
Asymmetric Catalysis
Highly Active Chiral Ruthenium-Based Metathesis Catalysts through a
Monosubstitution in the N-Heterocyclic Carbene**
Sascha Tiede, Anke Berger, David Schlesiger, Daniel Rost, Anja Lꢀhl, and Siegfried Blechert*
Asymmetric olefin metathesis has great synthetic potential as
N-aryl substituted complexes are in general far more
stable than their N-alkyl counterparts,[4,6] especially when
ꢀ
a result of its versatility in forming C C bonds under neutral
and mild conditions.[1] Stable ruthenium-based catalysts are of
special interest because of their ease of handling and their
functional-group tolerance.[2] All the chiral ruthenium meta-
thesis catalysts known to date derive from a,a’-disubstituted
diamines and therefore have an 3,4-disubstituted N-hetero-
cyclic carbene (NHC) ligand (Figure 1). In complexes with
monodentate ligands, such as 1 developed by Grubbs[3] as well
as in the variants by Collins,[4] the transfer of chirality to the
reactive metal center is accomplished through the hindered
rotation of N-aryl substituents. In case of the Hoveyda
complex 2, which includes bidentate ligands, transfer is
accomplished by stereocontrolled substitution of a halogen
ligand with a phenol derivative, which has the drawback of
significantly lowering the reactivity of the complexes.[5]
insertion into the C H bond which results in catalyst
ꢀ
deactivation is avoided by ortho-substitution.[7] The 3,4-
substituents in the NHC backbone have another function
besides induction of chirality: they can improve the stability
of ruthenium carbene complexes, as has been shown by both
density functional theory (DFT) calculations[8] and experi-
mental studies.[9] Chiral disubstituted complexes, such as 1,
show a rotation away from an orthogonal arrangement for
both aryl substituents, that is not found in their achiral
analogues, the Grubbs II and Hoveyda II precatalysts. This
rotation should, in our opinion, have an negative impact on
their reactivity.
During our studies of unsymmetrically substituted NHC
complexes we synthesized the first backbone-monosubsti-
tuted complexes which also bear two different N-aryl groups
and studied their properties and reactivity. Our goal was to
reach optimal transfer of chirality by using the C3 substituent
to induce a significant twist of the monosubstituted arene
ring.[10] In Addition, we employed a planar mesityl substituent
to avoid steric hindrance diminishing the reactivity.[11] We
herein report a new type of chiral catalyst, which is highly
stable and very reactive, showing both excellent E selectivity
and enantioselectivity in asymmetric ring-opening cross-
metathesis (AROCM).
We chose l-valine as starting material, which was first
coupled to an aryl halide using copper catalysis and sub-
sequently reduced to yield 4a,b (Scheme 1). 1-Iodo-2-isopro-
pylbenzene and 1,2-dibromobenzene were used as aryl
compounds. Metathesis catalysts bearing ortho-bromo sub-
stituents have not been described to date. The bromo
substituent offers several possibilities to introduce a range
of different substituents.
Figure 1. Chiral ruthenium metathesis (pre)catalysts 1 and 2 and our
compounds 3a–c; Mes=2,4,6-trimethylphenyl.
After preparation of sulfamidate[12] 5a,b nucleophilic
attack using boc-mesidine[13] leads to 6a,b. In case of
bromo-substituted diamine 6b, a phenyl substituent can be
introduced by Suzuki coupling. The phenyl is supposed to
hinder the rotation around the N–aryl bond but is less
sterically demanding than the isopropyl group. Synthesis of
the complexes 3a–c was by exchange of the phosphane ligand
on the Hoveyda I precatalyst for the NHC group. In total, all
three catalysts can be prepared in a few steps and in good
overall yields.
[*] S. Tiede,[+] A. Berger,[+] D. Schlesiger, D. Rost, A. Lꢀhl,[#]
Prof. Dr. S. Blechert
Institut fꢀr Chemie, Technische Universitꢁt Berlin
Strasse des 17.Juni 135, 10623 Berlin (Germany)
Fax: (+49)30-314-29745
E-mail: blechert@chem.tu-berlin.de
Homepage: http://www.chemie.tu-berlin.de/blechert
[#] Current address: Universitꢁt Karlsruhe
For first studies we chose the asymmetric ring-closing
metathesis (ARCM) of 8 as a model reaction, this is an
especially well studied reaction type.[3a,b,4,6] Reactivity tests
showed acceptable conversions using 5 mol% catalyst at
408C. The best enantioselectivities were achieved in CH2Cl2
using 3c (Table 1). Other solvents, such as THF, 2-methyl-
Engesserstrasse 15, 76131 Karlsruhe (Germany)
[+] These authors contributed equally to this work.
[**] We acknowledge support from the Cluster of Excellence “Unifying
Concepts in Catalysis” coordinated by the TU Berlin.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000940.
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Angew. Chem. Int. Ed. 2010, 49, 3972 –3975

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Chemie
Figure 2. Influence of styrene additives on the ARCM of 8. Conditions:
room temperature, 5 mol% 3c, and 5 equivalents additive.
Scheme 1. Catalyst synthesis: a) aryl halide, CuI, K2CO3, 1008C; a 71%,
b 56%; b) NaBH4, BF3·OEt2, 08C!668C, a 97%, b 85%; c) SOCl2, py,
ꢀ108C!room temperature, 12 h; a 86%, b 70%; d) RuCl3·H2O,
NaIO4, 08C, 3 h; a 91%, b 99%; e) HN(Boc)Mes, NaH, room temper-
ature, 12 h; TFA, room temperature, 12 h; a 82%, b 87%;
Table 2: Test of the catalysts in AROCM.
f) PhB(OH)2, 5 mol% [PdCl2(PPh3)2], toluene/EtOH, 1208C, 18 h,
95%; g) HC(OEt)3, NH4BF4, HCO2H, 1208C, 18 h; a 67%, b 71%,
c 92%; h) KHMDS, Hoveyda I catalyst, room temperature, 12 h;
a 56%, b 57%, c 60%. Boc=1,1-dimethylethoxycarbonyl; py=pyridine,
TFA=trifluoroacetic acid, KHMDS=potassium hexamethyldisilazane.
Entry Catalyst
R
T [8C] t [h] ee [%][a] E/Z[b]
1
2
3
4
5
6
7
8
9
10
1 mol% 3a
H
H
H
H
H
H
OMe
CF3
NO2
CO2Me
25
25
25
1
1
1
15
12
1
1
1
1
1
71
83
19:1
19:1
1 mol% 3b
1 mol% 3c
0.05 mol% 3c
1 mol% 3c
1 mol% 1
1 mol% 3c
1 mol% 3c
1 mol% 3c
1 mol% 3c
Table 1: The catalysts in ARCM.
88
>30:1
>30:1
>30:1
25
88[c]
93
ꢀ10
25
76[d]
81
1:1[3c]
25
25
25
25
14:1
30:1
n.d.
68
72
79
Catalyst
ee [%][a]
Conv. [%][b]
>30:1
3a
3b
3c
59
50
66
>98
58
87
[a] Determined by chiral HPLC, values refer to the E product. [b] Deter-
mined by GC/MS. [c] Z product: 65% ee. [d] Z product: 4% ee. n.d.=not
determined. The best values are highlighted.
1
[a] Determined by chiral GC. [b] Determined by H NMR spectroscopy.
shows no diastereoselectivity and in other cases led to 1.4:1
E/Z mixtures.[3c] The differences between the enantioselec-
tivities have to be noted, too. While 3c furnishes 88% ee for
the E isomer and 65% ee for the Z isomer (Table 2; entry 4), 1
leads to 76% ee for the E isomer and 4% ee for the Z isomer
(Table 2; entry 6). This great difference in enantioselectivity
was rationalized by the opening of the norborne-derivative
via a ruthenium benzylidene species. In our case, the
formation of a methylidene species prior to the norbornene
opening might occur, but no final conclusions about the
mechanism can be drawn from our results.
THF, C6F6, or toluene, did not lead to any improvements.
Reactions at lower temperatures with the aim of improving
enantioselectivity were prevented by the low conversions. In
the course of our studies we found that addition of styrene
derivatives significantly enhanced the reaction rate. Using
5 mol% 3c at room temperature with the addition of
5 equivalents of para-methoxystyrene leads to a conversion
from 8 into 9 of 70% after 2 h compared to 12% without
additive (Figure 2).[14] Lower temperatures did not lead to an
improvement in the ee values.
Much better results were achieved with ring-opening
cross-metathesis (AROCM) of norbornene derivatives. To
directly compare our catalysts with the Grubbs-type catalyst
1, we used styrene as the cross-partner for our reactions. In
contrast to the results of Grubbs et al.,[3c] we observed high E
selectivities in all cases. As a first reaction we chose the
AROCM of 10 (Table 2). Comparing catalysts 3a–c (Table 2;
entries 1–3), 3c again showed the best enantioselectivity and
furthermore an excellent E selectivity of over 30:1, while 1
Complete conversion of 10 could be achieved after 15 h
with only 0.05 mol% catalyst loading (Table 2; entry 4).[14]
Column chromatography furnished the product in 89% yield.
AROCM was also successful at low temperatures and led to
an increase in enantioselectivity: using 1 mol% 3c, 93% ee
was achieved with complete conversion after 12 h (Table 2;
entry 5).
These or even longer reaction times require a high
stability of the precatalyst in solution. Compound 3c did not
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3973

Communications
show any sign of decomposition even after 12 days at 408C in
CD2Cl2, while 1 started to decompose under these conditions
after a few hours. Compounds 3a,b were highly stable as well,
which is especially notable for ortho-bromo precatalyst 3b,
because comparable ruthenium complexes of the Hoveyda II
type bearing ortho-chlorophenyl substituents were not suit-
able for catalysis because of their instability.[15]
To study the electronic effects of the cross-partner, we
used styrene derivatives with different para substituents
(Table 2; entries 7–10).[16] Styrene was the best cross-partner.
No improvement in enantiomeric excess could be detected by
changing electron density of the styrene derivatives.
Despite being a Hoveyda II type catalyst, compound 3c
initiates very easily. During the test of more substrates, 3c
again showed high E selectivity paired with, in some cases,
excellent ee values (Table 3). Indications for the origin of the
Figure 3. Left: X-ray structure of 3c. Right: side-view of 3c and 3a
(styrene ether and mesityl group omitted for clarity).[18]
low initiation barrier allows reactions with very low catalyst
loadings and at low temperatures. The biphenyl structure,
novel to ruthenium catalysts metathesis chemistry, leads to
excellent enantioselectivities in AROCM. Further studies
concerning the reaction scope and catalyst immobilization are
underway.
Table 3: AROCM of different substrates with 3c.[a]
Entry
Substrate
T [8C] t [h] ee [%][b] E/Z[c]
Conv. [%][d]
1
2
25
ꢀ10
20
72
82
92
24:1 >98
13:1 >98
Experimental Section
Typical AROCM procedure: 3c (4.30 mg, 6.10 mmol, 0.05 mol%) was
added to a solution of 10 (2.00 g, 12.2 mmol, 1 equiv.) and styrene
(6.35 g, 61.0 mmol, 5 equiv.) in CH2Cl2 (174 mL, c = 0.07m) under a
nitrogen atmosphere. After 15 h stirring at room temperature,
ethylvinyl ether (0.1 mL) was added, the solvent evaporated, and
the compound was purified using column chromatography (SiO2,
cyclohexane/EtOAc). 2.90 g (10.8 mmol, 89% yield) product was
obtained.
3
4
25
ꢀ10
3.5
48
82
90
21:1 >98
23:1 >98
5
6
25 120
86
76
19:1
61
25
2
>30:1 >98
Received: February 15, 2010
Published online: May 5, 2010
7
8
ꢀ10
ꢀ10
12
12
70
60
21:1 >98
21:1 >98
Keywords: amino acids · asymmetric catalysis ·
N-heterocyclic carbenes · olefin metathesis · ruthenium
.
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ꢀ
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Chemie
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[17] Other unsymmetrically N-substituted NHC ligands with two
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[18] Crystallographic data for 3c: C27H42Cl2N2ORu, Mr = 702.70, P 21
21 21 P212121, a = 8.9798(11), b = 12.8985(15), c = 29.555(3) ꢀ,
a = b = g = 908, V= 3423.2(7) ꢀ3, Z = 4, 1calcd = 1.363 gcmꢀ3, m =
0.645 mmꢀ1, T= 150 K, qmax = 24.990, Rint = 0.153, R = 0.0739,
Rw = 0.1511. CCDC 765620 (3c) and CCDC 765621 ((R)-3a)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[10] Such results have been obtained both by DFT calculations
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Angew. Chem. Int. Ed. 2010, 49, 3972 –3975
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