Testing new ruthenium complexes bearing chiral 1,2,4-triazol-5-ylidene- ligands as catalysts for asymmetric olefin metathesis

Article abstract of DOI:10.1055/s-0033-1338877

New ruthenium complexes bearing chiral 1,2,4-triazol-5-ylidene ligands were obtained and tested in model asymmetric metathesis reactions. Low enantioselectivity in asymmetric ring-closing metathesis (ARCM) and moderate enantioselectivity in asymmetric rin

Full text of DOI:10.1055/s-0033-1338877

1250▌
CLUSTER
cTluestesrting New Ruthenium Complexes bearing Chiral 1,2,4-Triazol-5-ylidene
Ligands as Catalysts for Asymmetric Olefin Metathesis
Chiral 1,2,4-Triazol-5-ylidenes in Asymmetric Olefin Metathesis
Rafał Gawin,a Michał Pieczykolan,a Maura Malińska,b Krzysztof Woźniak,b Karol Grela*a
a
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax +48(22)343-2109; E-mail: klgrela@gmail.com
b
University of Warsaw, Faculty of Chemistry, Pasteura 1, 02-093 Warsaw, Poland
Received: 12.04.2013; Accepted after revision: 08.05.2013
t-Bu
t-Bu
R
R
Abstract: New ruthenium complexes bearing chiral 1,2,4-triazol-
5-ylidene ligands were obtained and tested in model asymmetric
metathesis reactions. Low enantioselectivity in asymmetric ring-
closing metathesis (ARCM) and moderate enantioselectivity in
asymmetric ring-opening/ring-closing metathesis (AROCM) was
observed.
i-Pr
N
N
N
N
Me
Ph
Cl
Ru
Cl
Ru
i-Pr
i-Pr
Cl
Cl
Ph
PCy3
PCy3
Key words: ruthenium, carbene complexes, NHC, olefin meta-
thesis, asymmetric catalysis
1 R = Ph
2 R–R = -(CH2)4-
3
i-Pr
Ph
In the past ten years, enantioselective olefin metathesis
has emerged as a powerful method for the synthesis of
carbon–carbon double bonds with simultaneous creation
of chirality elements under mild reaction conditions.
These advances have been possible due to intensive ef-
forts in the area of transition metal catalyst design. As it
was shown in a number of synthetic studies, chiral Mo-,
W-, and Ru-based catalysts used in asymmetric olefin
metathesis are complementary regarding scope and limi-
tations.1
N
N
I
N
N
Mes
Mes
Cl
Ru
O
Ru
O
O
Cl
Ph
5
4
N
N
Mes
N
N
In the ruthenium kingdom, since the first report2 on com-
plexes 1 and 2 (Figure 1), a number of catalysts bearing
NHC ligands derived from chiral 1,2-diamines have been
developed by Grubbs (2),2 Collins (3)3 and others. Hoveyda
introduced a conceptually unique class of Ru catalysts (4)
bearing C1-symmetric bidentate NHC ligands.4 Recently,
Blechert reported on the synthesis of complexes 5 and
6a,b with high activity and selectivity.5 Collins and
Blechert showed that C1-symmetric complexes give high-
er enantioselectivity in model reactions.3,5
Chiral 1,2,4-triazolium salts (e.g. 7a,6 Scheme 1) were
used with great success in a number of organocatalytic
transformations7 and were also recently applied as ligand
precursors for transition metal catalysis.8,9 This en-
couraged us to investigate the possibility of using them for
ruthenium-catalyzed asymmetric olefin metathesis.
Mes
Cl
Cl
Ru
O
Ru
Cl
Ph
Cl
PCy3
6a
6b
Figure 1 Selected chiral ruthenium metathesis (pre)catalysts
7a with KHMDS followed by addition of Grubbs first-
generation catalyst afforded complex 8a in 60% yield af-
ter column chromatography.
O
O
N
N
N
N
N
N
a, b
Mes
Ph
Mes
Cl
Ru
Cl–
Cl
Herein, we report on the synthesis of chiral ruthenium
metathesis (pre)catalysts bearing C1-symmetric 1,2,4-tri-
azol-5-ylidenes and their evaluation in model asymmetric
olefin metathesis reactions.
We started with precursor 7a6 (Scheme 1) because of its
rigid structure and commercial availability. Treatment of
PCy3
7a
8a
Scheme 1 Synthesis of complex 8a. Reagents and conditions: (a)
KHMDS, THF, r.t., 15 min; (b) Cl2(PCy3)2Ru=CHPh, THF, r.t., 30
min (60% two steps).
We were able to grow a single crystal from Et2O–MeOH
solvent mixture, so the solid-state structure of 8a has been
SYNLETT 2013, 24, 1250–1254
Advanced online publication: 28.05.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338877; Art ID: ST-2013-R0331-C
© Georg Thieme Verlag Stuttgart · New York

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Chiral 1,2,4-Triazol-5-ylidenes in Asymmetric Olefin Metathesis
1251
determined (Figure 2; see also Supporting Information for
details).
O
O
We noted some structural similarities between chiral
NHC ligands in compound 8a and in Blechert’s successful
catalysts 6a,b.5b Having the crystal structure of 8a in
hand, it would have been worth to compare it to the report-
ed structure of catalyst 6a. Unfortunately, only the crystal
structure of 6b was reported.5b Despite 8a being Grubbs-
type and 6b being a Hoveyda-type complex we decided to
compare those two structures anyway.10 The overlay of 8a
and 6b5b molecules is presented in Figure 3. The coordi-
nation geometry of ruthenium atom in 8a is more distorted
in comparison to 6b i.e. the C1–Ru1–P1 angle is 164.4(1)°
and 176.6(2)° for 8a and 6b, respectively. Modification of
the NHC ligand, e.g. position of chiral centre, leads to the
change of its orientation and the C1–N2–C14–C21 torsion
angle is equal to −90.1(5)° for 8a and −50.1(8)° for the
corresponding torsion angle of 6b. Therefore, the ob-
served Ru-H–C agostic interaction in the 6b precatalyst is
not present for 8a molecule.
9
10
Ph
+
Ph
O
O
O
O
O
O
11
12
Scheme 2 ARCM of 9 and AROCM of 11 as model reactions
oselectivity of reactions catalyzed by 8a was disappoint-
ingly low. It shall be noted, that complex 6a led to product
12 with 86% ee.5b It is known that even minor change in
the structure of a NHC ligand could dramatically affect
the properties of ruthenium carbene complexes.11 Unsatu-
ration of NHC backbone and additional nitrogen atom in
complex 8a may explain its different behavior compared
to 6a,b.
Table 1 ARCM of 9a
Entry
Catalyst
Conv. (%)b
ee (%)c
1
2
3
4
5f
8a
8b
8cd
8dd
3
>95
64
26
4e
9e
8
59
85
>98f
82f
a Reaction conditions: 5 mol% of Ru complex, CH2Cl2, 0.05 M, 40 °C,
3 h.
b Determined by GC.
c Determined by GC with a chiral column (Agilent® HP-CHIRAL-
20B).
d Reaction with in situ prepared catalyst.
e Excess of opposite enantiomer observed.
f See ref. 3.
Figure 2 ORTEP representation of complex 8a. Hydrogen atoms
have been omitted for clarity. Thermal ellipsoids are shown at the
50% probability level.
Although the enantioselectivity of both reactions was dis-
appointingly low with 8a, we considered this very initial
result of being promising. This encouraged us to synthe-
size analogues of complex 8a. First, we decided to synthe-
size a less rigid, yet bulky 1,2,4-triazol-5-ylidene ligand.
Starting from morpholinone 1312 derived from (S)-isoleu-
cine we obtained precursor 7b13 which was transformed to
catalyst 8b in 82% yield (Scheme 3).
Figure 3 Molecular overlay of 8a (red) and 6b (blue). For clarity
only Ru-NHC fragment is shown.
In the model reactions this catalyst (8b) also gave low ee:
4% and 24% (Table 1, entry 2 and Table 2, entry 2).
Therefore, after altering the left part of the NHC ligand,
and not achieving visible success, we decided to investi-
gate the influence of the flat N-aryl substituent modifica-
tion.
ARCM of 9 catalyzed by complex 8a proceed to full con-
version, however only 26% ee was observed for product
10 (Table 1, entry 1). Similarly, AROCM of 11 with sty-
rene (Table 2, entry 1) led to 19% ee only. Bearing in
mind the structural similarity to complexes 6a,b, enanti-
To do so, we used commercially available precursor 7c14
bearing N-pentafluorophenyl instead of N-mesityl group.
© Georg Thieme Verlag Stuttgart · New York
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R. Gawin et al.
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O
Similarly, starting from morpholinone 13 we obtained
precursor 7d16 which was transformed to silver complex
15 (Scheme 5). Reaction of 15 with Grubbs first-genera-
tion catalyst gave cleanly the expected product with full
conversion, but again after column chromatography com-
plex 8d was isolated with relatively low yield (55%).
N
O
O
a–d
O
N
N
N
Mes
Ph
e, f
N
N
NH
Cl
Ru
Mes
Cl–
Cl
PCy3
13
7b
8b
O
O
O
Scheme 3 Synthesis of precursor 7b and complex 8b. Reagents and
conditions: (a) Me3OBF4, CH2Cl2, r.t., 24 h; (b) sat. aq NaHCO3, 0 °C,
30 min, 96% (two steps); (c) MesNHNH2·HCl, HCl cat., MeOH, r.t.,
24 h; (d) (EtO)3CH, PhCl, 110 °C, 4 h, 33% (two steps); (e) KHMDS,
THF, r.t., 15 min; (f) Cl2(PCy3)2Ru=CHPh, THF, r.t., 30 min, 82%
(two steps).
N
a–c
d
NH
N
N
C6F5
–
BF4
13
7d
O
N
O
N
N
N
N
C6F5
N
N
e
C6F5
Ph
Table 2 AROCM of 11 with Styrenea
–
BF4
Cl
Ru
Ag
Entry
Catalyst
Conv. (%)b
ee (%)c
Cl
C6F5
PCy3
N
1
8a
>95
>95
17
19
N
8d
O
2
8b
8cd
8dd
6a
24
15
3
47e
72e
86f
75f
Scheme 5 Synthesis of complex 8d. Reagents and conditions: (a)
Me3OBF4, CH2Cl2, r.t., 24 h; (b) F5C6NHNH2, CH2Cl2, r.t., 24 h; (c)
(EtO)3CH, PhCl, 130 °C, 24 h, 72% (three steps); (d) Ag2O, CH2Cl2,
r.t., 72 h, 79%; (e) Cl2(PCy3)2Ru=CHPh, THF, r.t., 15 min, 55%.
4
57
5f
6f
78f
83f
6b
Unfortunately, complexes 8c and 8d containing C6F5-sub-
stituted 1,2,4-triazol-5-ylidene ligand proved to be less
stable as compared to their mesityl analogues 8a,b, which
makes their isolation and storage problematic. However,
since the reactions of silver complexes 14 and 15 with
Grubbs first-generation catalyst were completed (accord-
ing to NMR) within minutes at room temperature, leading
cleanly to the expected products, we decided to use in
model metathesis reactions in situ prepared complexes 8c
and 8d, instead of attempting to isolate and purify
them.4d,17
a Reaction conditions: 5 mol% of Ru complex, styrene (5 equiv),
THF, 0.2 M, 24 °C, 24 h.
b Determined by 1H NMR.
c Determined by HPLC with a chiral column (Daicel Chiralcel® OJ).
d Reaction with in situ prepared catalyst.
e Excess of opposite enantiomer observed.
f See ref. 5b.
Unfortunately, treatment of 7c with KHMDS followed by
addition of Grubbs first-generation catalyst led to the de-
sired complex 8c in a low yield, due to incomplete conver-
sion. Silver-NHC complexes are known to be good
carbene transfer reagents enabling mild introduction of
NHC to other metal complexes.4d,15 Treatment of 7c with
Ag2O afforded the silver complex 14 which was easily
transformed to the desired ruthenium complex 8c with full
conversion (Scheme 4). However due to low stability,
complex 8c was isolated with significantly lower yield
(52%).
To our disappointment, in the case of desymmetrization of
triene 9, alteration of the catalysts structure was not suc-
cessful and the modified catalysts exhibited lower selec-
tivity than the lead complex 8a. Slightly better results
were obtained in AROCM of 11. Introduction of N-penta-
fluorophenyl to the (pre)catalyst structure led to improve-
ment of selectivity and in the case of complex 8d product
12 was obtained with 72% ee (Table 2, entry 4); however
conversion of the reaction was moderate.
O
N
O
O
N
N
N
N
C6F5
b
a
N
N
N
N
C6F5
C6F5
Ph
Ag
Cl
Ru
–
BF4
–
BF4
Cl
C6F5
PCy3
N
N
N
7c
8c
O
14
Scheme 4 Synthesis of complex 8c. Reagents and conditions: (a) Ag2O, CH2Cl2, r.t., 72 h, 81%; (b) Cl2(PCy3)2Ru=CHPh, THF, r.t., 15 min,
52%.
Synlett 2013, 24, 1250–1254
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Chiral 1,2,4-Triazol-5-ylidenes in Asymmetric Olefin Metathesis
1253
Chem. Int. Ed. 2007, 46, 4534; Angew. Chem. 2007, 119,
4618. (h) Cortez, G. A.; Baxter, C. A.; Schrock, R. R.;
Hoveyda, A. H. Org. Lett. 2007, 9, 2871.
The change from N-mesityl group to N-pentafluorophenyl
group affects both steric and electronic factors of NHC li-
gand, but the exact reason for the improvement of stereo-
selectivity is unclear at the present stage of research.
Unfortunately we were unable to obtain a crystal of 8d
which may provide explanation for this observation.
(5) (a) Tiede, S.; Berger, A.; Schlesiger, D.; Rost, D.; Lühl, A.;
Blechert, S. Angew. Chem. Int. Ed. 2010, 49, 3972.
(b) Kannenberg, A.; Rost, D.; Eibauer, S.; Tiede, S.;
Blechert, S. Angew. Chem. Int. Ed. 2011, 50, 3299.
(6) Struble, J. R.; Bode, J. W. Org. Synth. 2010, 87, 362.
(7) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007,
107, 5606.
(8) (a) Strand, R. B.; Helgerud, T.; Solvang, T.; Dolva, A.;
Sperger, C. A.; Fiksdahl, A. Tetrahedron: Asymmetry 2012,
23, 1350. (b) Zhao, L.; Ma, Y.; Duan, W.; He, F.; Chen, J.;
Song, C. Org. Lett. 2012, 14, 5780.
(9) Ruthenium carbene complexes bearing achiral 1,2,4-triazol-
5-ylidene have been obtained. See: (a) Fürstner, A.;
Ackermann, L.; Gabor, B.; Goddard, R.; Lehmann, C. W.;
Mynott, R.; Stelzer, F.; Thiel, O. R. Chem. Eur. J. 2001, 7,
3236. (b) Trnka, T. M.; Morgan, J. P.; Sanford, M. S.;
Wilhelm, T. E.; Scholl, M.; Choi, T.-L.; Ding, S.; Day, M.
W.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 2546.
(10) Both Hoveyda- and Grubbs-type complexes 6a and 6b
gave very similar results in series of model AROCM
reactions, indicating that introduction of chelating 2-
isopropoxybenzylidene in place of Cy3P does not
The preliminary results obtained by us show that C1-sym-
metric 1,2,4-triazol-5-ylidenes can be used to form chiral
Ag and Ru complexes. Less stable Ru complexes 8c and
8d can be prepared by mixing two stable metallic precur-
sors and used in situ in asymmetric olefin metathesis. Al-
though observed enantioselectivity levels were lower than
those reported for other catalysts described in the litera-
ture,1a,2–5 we hope that further modifications may lead to
increasing the catalysts’ selectivity. Research in this di-
rection is ongoing in our laboratories and results will be
reported in due course.
Acknowledgment
R.G. thanks the Foundation for Polish Science (‘Ventures’ Pro-
gram) for financial support. The project ‘Ventures/2009-4/1’ was
executed within the ‘Ventures’ program of the Foundation for
Polish Science, co-financed by the European Union Regional Deve-
lopment Fund. R.G. and M.P. thank Dr Michał Michalak for dona-
tion of mesitylhydrazine, pentafluorohydrazine, and for GC
measurements.
substantially affect the enantioselectivity of the metathesis
reactions (cf. ref. 5b).
(11) (a) Samojłowicz, C.; Bieniek, M.; Grela, K. Chem. Rev.
2009, 109, 3708. (b) Vougioukalakis, G. C.; Grubbs, R. H.
Chem. Rev. 2010, 110, 1746.
(12) Norman, B. H.; Kroin, J. S. J. Org. Chem. 1996, 61, 4990.
(13) Synthesis of 7b: (S)-5-sec-Butylmorpholin-3-one (13; 230
mg, 1.46 mmol; see ref. 12) was dissolved in anhyd CH2Cl2
(7 mL) and Me3OBF4 (259 mg, 1.75 mmol) was added. The
mixture was stirred at r.t. for 24 h and then cooled to 0 °C.
Sat. aq NaHCO3 (10 mL) was added over 15 min and the
mixture was further stirred at r.t. for 30 min. The mixture
was extracted with CH2Cl2, and the combined organic layers
were washed with H2O and dried over Na2SO4. After
filtration, the solvent was removed under reduced pressure to
afford the crude (S)-3-sec-butyl-5-methoxy-3,6-dihydro-
2H-1,4-oxazine (239 mg, 96%) as a white solid which was
used in the next step without further purification.
Mesitylhydrazine hydrochloride (270 mg, 1.46 mmol) was
dissolved in anhyd MeOH (6 mL). The crude (S)-3-sec-
butyl-5-methoxy-3,6-dihydro-2H-1,4-oxazine (239 mg,
0.48 mmol) was added in one portion followed by HCl (4 M
in 1,4-dioxane; 36 μL, 0.20 mmol, 0.100 equiv) and the
reaction mixture was stirred at r.t. for 24 h. The solvent was
evaporated to give a yellow solid which was dried in high
vacuum. The residue was suspended in chlorobenzene (1.5
mL) and triethyl orthoformate (2 mL, 11.7 mmol) was
added. The mixture was stirred for 4 h at 110 °C and
concentrated in vacuum. After purification by column
chromatography (CH2Cl2–MeOH = 99:1 to 95:5) the desired
product was obtained as an off-white solid (160 mg, 33%).
(14) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem.
2005, 70, 5725.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
References and Notes
(1) For reviews on asymmetric olefin metathesis, see: (a) Kress,
S.; Blechert, S. Chem. Soc. Rev. 2012, 41, 4389. (b) Schrock,
R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42,
4592. (c) Hoveyda, A. H.; Schrock, R. R. Chem. Eur. J.
2001, 7, 945. (d) Hoveyda, A. H.; Zhugralin, A. R. Nature
(London) 2007, 450, 243. (e) Cortez, G. A.; Baxter, C. A.;
Schorck, R. R.; Hoveyda, A. H. Org. Lett. 2007, 9, 2871.
(2) (a) Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett.
2001, 3, 3225. (b) Funk, T. W.; Berlin, J. M.; Grubbs, R. H.
J. Am. Chem. Soc. 2006, 128, 1840. (c) Berlin, J. M.;
Goldberg, S. D.; Grubbs, R. H. Angew. Chem. Int. Ed. 2006,
45, 7591; Angew. Chem. 2006, 118, 7753.
(3) (a) Fournier, P.-A.; Collins, S. K. Organometallics 2007, 26,
2945. (b) Fournier, P.-A.; Savoie, J.; Stenne, B.; Bødard, M.;
Grandbois, A.; Collins, S. K. Chem. Eur. J. 2008, 14, 8690.
(c) Grandbois, A.; Collins, S. K. Chem. Eur. J. 2008, 14,
9323. (d) Savoie, J.; Stenne, B.; Collins, S. K. Adv. Synth.
Catal. 2009, 351.
(4) (a) Van Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 4954. (b) Van
Veldhuizen, J. J.; Gillingham, D. G.; Garber, S. B.; Kataoka,
O.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 12502.
(c) Gillingham, D. G.; Kataoka, O.; Garber, S. B.; Hoveyda,
A. H. J. Am. Chem. Soc. 2004, 126, 12288. (d) Van
Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda,
A. H. J. Am. Chem. Soc. 2005, 127, 6877. (e) Giudici, R. E.;
Hoveyda, A. H. J. Am. Chem. Soc. 2007, 129, 3824.
(f) Gillingham, D. G.; Hoveyda, A. H. Angew. Chem. Int.
Ed. 2007, 46, 3860; Angew. Chem. 2007, 119, 3934.
(g) Cortez, G. A.; Schrock, R. R.; Hoveyda, A. H. Angew.
(15) (a) Arnold, P. L. Heteroat. Chem. 2002, 13, 534. (b) Larsen,
A. O.; Leu, W.; Oberhuber, C. N.; Campbell, J. E.; Hoveyda,
A. H. J. Am. Chem. Soc. 2004, 126, 11130.
(16) Synthesis of 7d: (S)-5-sec-Butylmorpholin-3-one (13; 692
mg, 4.40 mmol) was dissolved in anhyd CH2Cl2 (10 mL) and
Me3OBF4 (651 mg, 4.4 mmol) was added. The mixture was
stirred at r.t. for 24 h. Pentafluorophenyl hydrazine (872 mg,
4.40 mmol) was added in one portion and the mixture was
further stirred for 24 h at r.t. The solvent was evaporated and
© Georg Thieme Verlag Stuttgart · New York
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1254
R. Gawin et al.
CLUSTER
residue was dried in high vacuum. Chlorobenzene (5 mL)
and triethyl orthoformate (1.8 mL, 11.0 mmol) were added
and the mixture was heated to 130 °C for 24 h and then
stored overnight in fridge. The precipitated crystals were
filtered off and washed with toluene and dried in high
vacuum to give the desired product as a white solid (1.40 g,
72%).
mol%) was added under argon and the reaction mixture was
stirred at r.t. for 15 min. After that time the reaction mixture
was transferred to a solution of 11 (32.8 mg, 0.2 mmol) and
styrene (104.2 mg, 1.0 mmol) in anhyd THF (0.5 mL) and
the formed mixture was stirred at 24 °C for 24 h under an
argon atmosphere. The reaction was quenched by addition of
ethyl vinyl ether and the reaction mixture was concentrated
under vacuum. Conversion was determined by 1H NMR
while the ee value was determined by HPLC analysis using
a chiral column (Daicel Chiralcel® OJ).
(17) AROCM of 11 with In Situ Prepared Catalyst 8d: To a
solution of bis(tricyclohexylphosphine)benzylidene
ruthenium dichloride (8.2 mg, 0.01 mmol, 5 mol%) in anhyd
THF (0.5 mL) silver complex 15 (6.2 mg, 0.007 mmol, 3.5
Synlett 2013, 24, 1250–1254
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