Synthesis of a new chiral N,N,N-tridentate pyridinebisimidazoline ligand library and its application in Ru-catalyzed asymmetric epoxidation

Article abstract of DOI:10.1021/ol050821e

(Chemical Equation Presented) A small ligand library of chiral tridentate N,N,N-pyridinebisimidazolines have been synthesized for the first time. This new class of ligands can be easily tuned and synthesized on multi g-scale. The usefulness of the ligands is shown in the ruthenium-catalyzed asymmetric epoxidation with hydrogen peroxide as oxidant. Excellent yields (>99%) and good enantioselectivities (up to 71% ee) have been obtained for the epoxidation of aromatic olefins.

Full text of DOI:10.1021/ol050821e

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3393-3396
Synthesis of a New Chiral
N,N,N-Tridentate Pyridinebisimidazoline
Ligand Library and Its Application in
Ru-Catalyzed Asymmetric Epoxidation
Santosh Bhor, Gopinathan Anilkumar, Man Kin Tse, Markus Klawonn,
Christian Do1bler, Bianca Bitterlich, Anne Grotevendt, and Matthias Beller*
Leibniz-Institut fu¨r Organische Katalyse (IfOK) an der UniVersita¨t Rostock e.V.,
Albert-Einstein-Strasse 29A, D-18059 Rostock, Germany
matthias.beller@ifok.uni-rostock.de
Received April 15, 2005
ABSTRACT
A small ligand library of chiral tridentate N,N,N-pyridinebisimidazolines have been synthesized for the first time. This new class of ligands can
be easily tuned and synthesized on multi g-scale. The usefulness of the ligands is shown in the ruthenium-catalyzed asymmetric epoxidation
with hydrogen peroxide as oxidant. Excellent yields (>99%) and good enantioselectivities (up to 71% ee) have been obtained for the epoxidation
of aromatic olefins.
Transition metal-catalyzed asymmetric reactions offer an
efficient and elegant possibility for the synthesis of enan-
tiomerically pure compounds.1 In general, the choice and
synthesis of a suitable chiral controller ligand is the crucial
step in the development of a new catalyst for stereoselective
reactions. Clearly, a multitude of chiral mono-, bi- and
multidentate ligands with P, N, O, and other coordinating
atoms are known today and used extensively for all kinds
of catalytic reactions. Prominent examples of so-called
privileged ligand classes include the salens,2 bisoxazolines,3
phosphinooxazolines,4 tartrate derivatives,5 and cinchona
alkaloids.6 Nevertheless, there is still an increasing need for
new and improved ligands. State-of-the-art chiral ligands7
(3) (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron:
Asymmetry 1998, 8, 1-45. (b) Jorgensen, K. A.; Johannsen, M.; Yao, S.;
Audrain, H.; Thornauge, J. Acc. Chem. Res. 1999, 32, 605-613.
(4) For a review, see: Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000,
33, 336-345.
(5) (a) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; Wiley-VCH: New York, 1993; Chapter 4.1. (b)
Katsuki, T.; Martin, V. S.; Org. React. 1996, 48, 1-299. (c) Seebach, D.;
Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001, 1, 92-139.
(6) (a) Kolb, H. C.; Van Nieuwenzhe, M. S.; Sharpless, K. B. Chem.
ReV. 1994, 94, 2483-2547. (b) Beller, M.; Sharpless, K. B. In Applied
Homogeneous Catalysis with Organometallic Compounds, Vol. 2; Cornils,
B.; Herrmann, W. A., Eds.; VCH: Weinheim, 1996; pp 1009-1024. (c)
Kolb, H. C.; Sharpless, K. B. In Transition Metals for Organic Synthesis,
Vol. 2; Beller, M.; Bolm, C., Eds.; VCH: Weinheim, 1998; pp 219-242.
(d) Marko´, I. E.; Svendsen, J. S. In ComprehensiVe Asymmetric Catalysis
II; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
pp 713-787. (e) Bolm, C.; Hildebrand, J. P.; Mun˜iz, K. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: New York, 2000; pp
399-428.
(1) (a) Noyori, R., Ed. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994. (b) Beller, M.; Bolm, C., Eds. Transition Metals
for Organic Synthesis, 2nd ed.; Wiley-VCH: Weinheim, 2004. (c) Jacobsen,
E. N.; Pfaltz, A.; Yamamoto, H., Eds. ComprehensiVe Asymmetric Catalysis,
Springer: Berlin, 1999.
(2) (a) Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
Wiley-VCH: New York, 1993; Chapter 4.2. (b) Katsuki, T. In Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York,
2000; pp 287-325. (c) Katsuki, T. AdV. Synth. Catal. 2002, 344, 131-
147.
10.1021/ol050821e CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/09/2005

should offer the user a series of advantages: obviously, it
should give highly selective and active as well as productive
catalysts. In addition, the ligand should be conveniently
prepared from mg- to kg-scale, and the synthesis should be
economically feasible. Unfortunately, each catalytic reaction
needs its own optimized ligand. To find the optimal catalyst
for a certain substrate the preparation of ligand libraries with
the same basic ligand skeleton should be possible without
problems. However, the systematic modification of the
structure of new ligands is often difficult and time-consum-
ing.
Herein, we report a new class of chiral ligands, which is
simply synthesized and can be easily varied by remote
functionalizations to allow for the preparation of ligand
libraries in a fast and practical manner.
The starting point of this work was our studies on
ruthenium-catalyzed epoxidation of olefins with C2-sym-
metric pyridinebisoxazolines (pybox) as the chiral ligand.8
While synthesizing new pybox ligands, we realized that the
preparation of such a ligand library is limited and time-
consuming due to the difficulty of functionalizations of the
ligand backbone and stepwise formation of the oxazoline
moiety.9
Treatment of 1 with a catalytic amount of sodium in
anhydrous methanol followed by neutralization with acetic
acid and removal of methanol under reduced pressure,
afforded the bisimidate 2 as a pale yellow solid in quantitative
yield.11
Condensation of 2 with chiral diamines such as R,R-1,2-
diaminocyclohexane and R,R-1,2-diphenylethylene-diamine
furnished the corresponding pyridine-bisimidazoline ligands
3 and 4 in good to excellent yield. The pybims 3 and 4 are
stable to air and moisture and offer numerous possibilities
for further modification at the amine functionality. Note-
worthy, the synthesis of 4 has been performed without
problems on 10 g-scale.12
To demonstrate the usefulness of the concept a small
library of 14 pybims was prepared from 3 and 4 (Table 1).
Treatment with benzyl bromide in the presence of sodium
hydride gave the corresponding ligands 5a and 6a in 68%
and 65% yields respectively (Table 1, entry 1 and 3).
The reaction of tosyl chloride (Table 1, entry 2 and 4),
carbonyl chlorides (Table 1, entry 5-10, and 13) and
chloroformates (Table 1, entry 11, 12, and 14) with 3 or 4
gave the corresponding pybim ligands 5b, 6b-l in moderate
to very good yield (60 to 97%) by using DMAP in
dichloromethane at 0 °C to room temperature.
We thought that introducing a second nitrogen atom in
place of oxygen of pyridinebisoxazoline ligands would
provide a more flexible ligand scaffold, which might be
easily varied by N-alkylation, N-arylation, and N-acylation
to tune the reactivity as well as stereoselectivity in catalytic
asymmetric reactions (Figure 1).
For the preparation of 6k, (S)-methoxy-R-methyl-2-
naphthalene acetyl chloride was prepared by refluxing the
corresponding acid in CHCl3 with excess of thionyl chloride
(Table 1, entry 13).
With the newly developed ligands in hand, we looked for
a suitable test reaction to demonstrate that substitution of
imidazoline NH group has a significant influence on
catalysis. In principle, pybim-type ligands should be useful
for any reaction, which use pybox ligands, e.g., aziridinations,
epoxidations, carbene reactions, addition of nucleophiles to
carbonyl groups, etc.10 Among the various catalytic reactions
known for pybox ligands asymmetric epoxidations with
hydrogen peroxide are among the most challenging meth-
ods.13 Therefore, we decided to study the behavior of the
(10) For recent examples of catalysis with pybox derivatives, see: (a)
Pfaltz, A. Acc. Chem. Res. 1993, 26, 339-345. (b) Nishiyama, H.; Itoh,
Y.; Matsumoto, H.; Park, S.-B.; Itoh, K. J. Am. Chem. Soc. 1994, 116,
2223-2224. (c) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron:
Asymmetry 1998, 9, 1-45. (d) Sekar, G.; DattaGupta, A.; Singh, V. K. J.
Org. Chem. 1998, 63, 2961-2967. (e) Johnson, J. S.; Evans, D. A. Acc.
Chem. Res. 2000, 33, 325-335. (f) Zhao, C.-X.; Duffey, M. O.; Taylor, S.
J.; Morken, J. P. Org. Lett. 2001, 3, 1829-1831. (g) Zhou, J.; Fu, G. C. J.
Am. Chem. Soc. 2004, 126, 1340-1341. (h) Cuervo, D.; Gamasa, M. P.;
Gimeno, J. Chem. Eur. J. 2004, 10, 425-432. (i) Desimoni, G.; Faita, G.;
Quadrelli, P. Chem. ReV. 2003, 103, 3119-3154.
Figure 1. From pybox to pybim ligands.
Despite the importance of pybox ligands for numerous
stereoselective reactions,10 to the best of our knowledge
similar chiral pyridinebisimidazoline ligands, here abbrevi-
ated as pybim, have not been synthesized and applied in
asymmetric catalysis.
(11) (a) Mu¨ller, P.; Bolea, C.; HelV. Chim. Acta. 2001, 84, 1093-1111.
(b) Bastero, A.; Claver, C.; Ruiz, A.; Castillon, S.; Daura, E.; Bo, C.;
Zangvando, E. Chem. Eur. J. 2004, 10, 3747-3760.
The synthesis of the pybim scaffold is easily done from
commercially available 2,6-dicyanopyridine 1 in two steps.
(12) A 100 mL pressure tube was charged with bis-imidate 2 (4.55 g,
23.6 mmol), (R, R)-1, 2-diphenyl ethylenediamine (10.0 g, 47.1 mmol) and
75 mL of dichloromethane. The resulting mixture was stirred at reflux for
2 days. Then 50 mL of water was added and the phases were separated;
the aqueous phase was extracted with dichloromethane (2 × 50 mL). The
combined organic layers were dried over MgSO4 and the solvents were
removed in vacuo to give a light yellow solid, which was purified by
crystallization (ether/ethyl acetate) to give 4 in 62% yields (7.6 g, 3.46
mmol).
(13) For reviews of H2O2 as epoxidation oxidant see: (a) Grigoropoulou,
G.; Clark, J. H.; Elings, J. A. Green Chem. 2003, 5, 1-7. (b) Lane, B. S.;
Burgess, K. Chem. ReV. 2003, 103, 2457-2473. For a commentary, see:
(c) Beller, M. AdV. Synth. Catal. 2004, 346, 107-108.
(7) For a discussion on the “ideal catalyst”, see: Gladysz, J. A. Pure
Appl. Chem. 2001, 73, 1319-1324.
(8) (a) Tse, M. K.; Bhor, S.; Klawonn, M.; Do¨bler, C.; Beller, M.
Tetrahedron Lett. 2003, 44, 7479-7483. (b) Bhor, S.; Tse, M. K. Klawonn,
M.; Do¨bler, C.; Ma¨gerlein, W.; Beller, M. AdV. Synth. Catal. 2004, 346,
263-267. (c) Klawonn, M.; Tse, M. K.; Bhor, S.; Do¨bler, C.; Beller, M. J.
Mol. Catal. A 2004, 218, 13-19. (d) Tse, M. K.; Do¨bler, C.; Bhor, S.;
Klawonn, M.; Ma¨gerlein, W.; Hugl, H.; Beller, M. Angew. Chem., Int. Ed.
2004, 43, 5255-5260.
(9) (a) Desimoni, G.; Faita, G.; Quadrrelli, P. Chem. ReV. 2003, 103,
3119-3154. (b) Nishiyama, H. AdV. Catal. Proc. 1997, 2, 153-188.
3394
Org. Lett., Vol. 7, No. 16, 2005

Table 1. Synthesis of a Pybim Library
Reagents and conditions: aCH2Cl2, reflux, 2 d; b 2.5 equiv. NaH, THF, 0 °C to room temperature, 4 h; c 3.0 equiv. DMAP, CH2Cl2, 0 °C to room
temperature, 5 h.
new ligands in the ruthenium-catalyzed asymmetric epoxi-
dation8,14 of stilbene with hydrogen peroxide. For this
purpose, the pyridinebisimidazoline ligands 5a-b and 6a-l
were transformed into the novel class of Ru(pybim)(pydic)
complexes 7a-b and 8a-l, using disodium pyridine-2,6-
dicarboxylate and [Ru(p-cymene)Cl2]2 (Scheme 1).15 The
catalytic reactions were run at room temperature in the
presence of 5 mol% of Ru-complex using 3 equiv. of H2O2
(30% in water), which was slowly dosed into the reaction
mixture.
As shown in Table 2, all the Ru(pybim)(pydic) complexes
catalyzed the epoxidation of trans-stilbene. It is important
to note that the enantioselectivity and reactivity of the catalyst
is largely dependent on the respective substituent on the
nitrogen of the imidazoline ring (remote functionality) of
Ru(pybim)(pydic) complex. This is a clear proof of our
concept and by steric and electronic tuning at this position
an optimization of the catalyst is possible. Similar effects
Scheme 1. Synthesis of Ru(pybim)(pydic) Complexes
(14) For a review using Ru complexes for epoxidation reactions see:
(a) Barf, G. A.; Sheldon, R. A. J. Mol. Catal. 1995, 102, 23-39. Recent
achievements in Ru-based epoxidations with different oxidants, see: (b)
End, N.; Pfaltz, A. Chem. Commun. 1999, 589-590. (c) Gross, Z.; Ini, S.
Org. Lett. 1999, 1, 2077-2080. (d) Pezet, F.; A¨ıt-Haddou, H.; Daran, J.-
C.; Sadaki, I.; Balavoine, G. G. A. Chem. Commun. 2002, 510-511. Recent
examples using Ru salen complexes, see: (e) Takeda, T.; Irie, R.; Shinoda,
Y.; Katsuki, T. Synlett. 1999, 1157-1159. (f) Nakata, K.; Takeda, T.;
Mihara, J.; Hamada, T.; Irie, R.; Katsuki, T. Chem. Eur. J. 2001, 7, 3776-
3782. (g) Berkessel, A.; Kaiser, P.; Lex, J. Chem. Eur. J. 2003, 9, 4746-
4756.
Note: For R1 substituent see Table 1.
(15) Nishiyama, H.; Shimada, T.; Itoh, H.; Sugiyama, H.; Motoyama,
Y. Chem. Commun. 1997, 1863-1864.
Org. Lett., Vol. 7, No. 16, 2005
3395

Table 2. Ru(pybim)(pydic)-Catalyzed Asymmetric Epoxidation
of trans-Stilbene Using H2O2 as Oxidanta
Table 3. Catalyst Scopea
entry
catalyst
time (h)
conv. (%)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
7a
7b
8a
8b
8c
8d
8e
8f
8 g
8h
8i
8j
8k
8l
16
12
16
4
85
100
90
79
93
79
63
90
>99
78
>99
91
1
8
11
21
34
38
33
52
56
28
60
71
69
71
77
12
12
12
12
12
12
12
12
12
12
100
100
100
100
100
100
100
100
100
100
97
>99
>99
94
a Reaction conditions: In a 25 mL Schlenk tube Ru-catalyst 8l (0.025
mmol) and substrate (0.5 mmol) were dissolved in tert-amyl alcohol (9
mL). Dodecane (GC internal standard, 100 µL) was added. To this mixture
a solution of hydrogen peroxide (170 µL, 1.5 mmol) in tert-amyl alcohol
(830 µL) was added over a period of 12 h by a syringe pump. b Determined
by comparing with authentic samples on GC-FID. c Determined by HPLC.
97
a Reaction conditions: In a 25 mL Schlenk tube Ru-complex (0.025
mmol) and trans-stilbene (0.5 mmol) were dissolved in tert-amyl alcohol
(9 mL). Dodecane (GC internal standard, 100 µL) was added. To this
mixture a solution of hydrogen peroxide (170 µL, 1.5 mmol) in tert-amyl
alcohol (830 µL) was added over a period of 12 h by a syringe pump.
b Determined by comparing with authentic samples on GC-FID. c Deter-
mined by HPLC and the major enantiomer of trans-stilbene oxide had
1R,2R-configuration.
In summary, we have disclosed a novel class of chiral
tridentate, pyridinebisimidazoline ligands (pybims). The key
building blocks 3 and 4 are conveniently synthesized in two
steps from commercially available starting materials. Similar
compounds should be available by using other chiral 1,2-
diamines.
might be expected for other catalytic reactions which proceed
in the presence of pybox ligands, too.
Ru-complexes derived from most of the new ligands are
effective catalysts for asymmetric epoxidation of alkenes with
hydrogen peroxide. Advantageously, compared to the well-
known pybox ligands systematic modification of the catalyst
system is possible due to the presence of the imidazoline
NH-groups. As proof of concept it is shown that these remote
functionalizations have an important impact on the outcome
of catalytic epoxidation reactions.
More specifically the Ru(R,R-cyclohexyl-N,N′-Bn2-py-
bim)(pydic) complex 7a gave a racemic mixture of trans-
stilbene oxide (79%) with low reactivity (Table 2, entry 1),
while Ru-complexes which were synthesized from tetra-
phenyl pybim ligands with N-benzoyl protection 8a-g led
to good to excellent yields (78 f 99%) and significant
enantioselectivities (33-56% ee) (Table 2, entries 5-9). Best
results for the epoxidation of trans-stilbene were obtained
applying the carbamate-functionalized complexes 8j and 8l.
Here, the enantioselectivity was increased up to 71% ee for
trans-stilbene oxide (97 f 99% yield) (Table 2, entry 12
and 14). Interestingly, also 8k, functionalized with the
sterically bulky and flexible chiral (S)-2-(6-methoxynaph-
thyl)propionic acid gave 69% ee for trans-stilbene oxide
(Table 2, entry 13).
Acknowledgment. This work has been supported by the
State of MecklenburgsWestern Pommerania. We thank Mrs.
C. Mewes, Mrs. H. Baudisch, Mrs. A. Lehmann, and Mrs.
S. Buchholz (all IfOK) for their excellent technical and
analytical support. Dr. H. Hugl and Dr. W. Ma¨gerlein
(LANXESS) are thanked for general discussions.
Next, some preliminary substrate variation was done and
catalyst 8l was applied to different olefins (Table 3). To our
delight, mono-, di-, and trisubstituted aromatic olefins gave
good to excellent yields (76 f 99%) and moderate to good
enantioselectivity (42-68%) (Table 3). Specifically, the
result for styrene (Table 3, entry 1) is promising for further
development of this type of catalyst since it is one of the
most difficult substrates for epoxidation using hydrogen
peroxide and often found in the literatures with low yields
and enantioselectivity.16 To the best of our knowledge, the
maximum enantioselectivity is only 59% for styrene oxide
using hydrogen peroxide as the oxidant.8d
Supporting Information Available: Experimental pro-
cedures and characterization of all ligands, complexes and
epoxides. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL050821E
(16) (a) Stoop, R. M.; Mezzetti, A. Green Chem. 1999, 39-41. (b) Stoop,
R. M.; Bachmann, S.; Valentini, M.; Mezzetti, A. Organometallics 2000,
19, 4117-4126. (b) Bolm, C.; Kadereit, D.; Valacchi, M. Synlett. 1997,
687-688. (c) Bolm, C.; Meyer, N.; Raabe, G.; Weyhermu¨ller, T.; Bothe,
E. Chem. Commun. 2000, 2435-2436. (d) Kureshy, R. I.; Khan, N. H.;
Abdi, S. H. R.; Patel, S. T.; Jasra, R. V. Tetrahedron: Asymmetry 2001,
12, 433-437.
3396
Org. Lett., Vol. 7, No. 16, 2005