A new chiral ruthenium complex for catalytic asymmetric cyclopropanation

Article abstract of DOI:10.1016/S0040-4039(02)00317-9

A new chiral ruthenium complex 6, featured with an N,O-mixed polydentate ligand, was synthesized and characterized. This ruthenium complex showed high efficiency in catalytic cyclopropanations of alkenes with diazoacetates. High trans/cis selectivity and enantioselectivity (up to 96%) were achieved with the readily accessible ethyl diazoacetate as the reagent.

Full text of DOI:10.1016/S0040-4039(02)00317-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3075–3078
A new chiral ruthenium complex for catalytic asymmetric
cyclopropanation
Wenjun Tang, Xinquan Hu and Xumu Zhang*
Department of Chemistry, The Pennsylvania State University, University Park, PA 1680, USA
Accepted 14 February 2002
Abstract—A new chiral ruthenium complex 6, featured with an N,O-mixed polydentate ligand, was synthesized and characterized.
This ruthenium complex showed high efficiency in catalytic cyclopropanations of alkenes with diazoacetates. High trans/cis
selectivity and enantioselectivity (up to 96%) were achieved with the readily accessible ethyl diazoacetate as the reagent. © 2002
Elsevier Science Ltd. All rights reserved.
,
Metal-catalyzed asymmetric cyclopropanation remains
of great interest due to its versatile applications in
synthetic organic chemistry.1 Although several excellent
metal catalysts such as Cu-salicylaldimine,2a Cu-semi-
corrin,2b Cu-bisoxazoline,2c and chiral dirhodium sys-
tem,2e–f have been developed for asymmetric
intermolecular or intramolecular cyclopropanations,
the development of new catalysts in terms of low
catalyst loading, high diastereoselectivity, good enan-
tioselectivity, and the use of readily accessible and
cheap diazo compounds, remains an important goal.
Several successful chiral Ru catalysts have also been
developed for intermolecular cyclopropanation of
olefins and diazoacetates. Among them are Nishiyama’s
Ru Pybox system,3 Katsuki’s Ru salen system,4 and
Scott’s Ru Schiff-base complex.5 Herein we wish to
report a novel and efficient chiral ruthenium catalyst 6
for intermolecular cyclopropanation of olefins with dia-
zoacetates. Low catalyst loading (1 mol%), good trans/
cis selectivity (90/10), and high enantioselectivities (up
to 96%) have been achieved with the readily available
ethyl diazoacetate as the reagent. Possible interaction
between the esters of carbenes and the hydroxyl groups
in 6 is a novel feature of our catalytic system.
presence of 4 A molecular sieves, ligand 3 was obtained
in 75% yield with a high purity (>95%).7 We hoped to
make ruthenium complex 4 through the reaction of
[RuIICl2(p-cymene)]2, pyridine, and ligand 3 in i-
propanol. However, our results showed that a different
air-stable Ru complex 5 was formed. The structure of 5
was characterized by NMR and MS analysis, and its
naphthol protons were also examined by H-D
exchange.8 We envisioned that the scaffold of 5 might
be good for catalytic cyclopropanation reaction. How-
ever, 5 showed no reactivity for cyclopropanation of
styrene and ethyl diazoacetate at room temperature. In
order to make an active Ru catalyst for cyclopropana-
tion, we employed bulkier pyridine derivatives for the
preparation of Ru catalysts. Surprisingly, when we used
2,6-dichloropyridine or 2-chloropyridine as the base
and methanol as the solvent, a purple precipitate was
formed (Scheme 2). This precipitate was identified to
have no pyridine moiety according to its 1H NMR
spectrum, while one mol equivalent of methanol was
observed. We thus assumed that the structure of the
precipitate was a methanol-coordinated Ru complex 6.9
To further corroborate the assignment, 6 was treated
with pyridine in dichloromethane solution, leading to
the formation of Ru complex 5. It is noteworthy that
2,6-dichloropyridine or 2-chloropyridine did not
exchange with the coordinated methanol of 6 in the
reaction to form pyridine coordinated Ru complex like
5. We consider that this could be attributed to the steric
effect of the substituted pyridines. The steric bulk of the
ligand 3 might only allow the coordination of unhin-
dered pyridine to the ruthenium atom. Complex 6 is
stable under N2 atmosphere and can be stored for a
long time. No sign of decomposition was observed
according to its NMR after it was stored under N2 for
6 months.
In the course of exploring ligands with a well-defined
chiral environment, we designed an N,O-mixed
polydentate ligand 3. This ligand can be directly pre-
pared from chiral 2-amino-2%-hydroxy-1,1%-binaphthyl 1
(NOBIN)6 and 2,6-pyridinedimethanal 2 (Scheme 1).
By refluxing the mixture of 1 and 2 in i-propanol in the
* Corresponding author. Tel.: 1-814-863-5614; fax: +1-814-863-8403;
e-mail: xumu@chem.psu.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00317-9

3076
W. Tang et al. / Tetrahedron Letters 43 (2002) 3075–3078
N
N
N
NH2
OH
4A MS
i-Propanol
75%
+
OHC
OH
HO
N
CHO
3
2
1
N
N
O
N
O
Ru
N
[RuCl2(cymene)]2
4
pyridine
i-propanol
N
Cl
N
N
Ru
OH
HO
Cl
N
5
Scheme 1.
N
N
Cl
N
N
N
N
[RuCl2(cymene)]2
2-chloropyridine or
2, 6-dichloropyridine
Ru
OH
HO
OH
HO
Cl
HO
CH3
CH3OH
6
3
N
Cl
N
N
pyridine
Ru
OH
HO
Cl
N
5
Scheme 2.
trans/cis selectivity (90:10) and enantioselectivity (trans
ee: 97%; cis ee: 90%) were achieved (entry 1). We thus
employed CH2Cl2 as the solvent to screen different
diazoacetates (Table 2). It is well documented that
bulkier diazoacetates such as tert-butyl diazoacetate or
menthyl diazoacetate give better enantioselectivity in
most intermolecular cyclopropanations.1a However,
bulkier diazoacetates eroded the yield as well as the
enantioselectivity in our system (entry 7 versus entries
The Ru complex 6 was then tested for catalytic cyclo-
propanation reaction. It is found that 6 is a highly
active catalyst for cyclopropanation of styrene with
ethyl diazoacetate. In the presence of 1 mol% of 6, the
cyclopropanation proceeded smoothly to afford 2-
phenylcyclopropanecarboxylates 8 and 9 in high yields.
trans/cis Selectivity and enantioselectivity were solvent
dependent (Table 1). High selectivities were observed
with a non-coordinated solvent. In CH2Cl2, the best

W. Tang et al. / Tetrahedron Letters 43 (2002) 3075–3078
3077
Table 1. Solvent effect in cyclopropanation of styrene with ethyl diazoacetate
Ph
1 mol% 6
CO2Et
CO2Et
+
+
N2CHCO2Et
Ph
Solvent
8
9
Entry
Solvent
Ratio (trans:cis)
Ee (%)
cis
trans
1a
2
3
CH2Cl2
90:10
88:12
89:11
83:17
97
96
95
64
90
87
85
5
ClCH2CH2Cl2
Toluene
THF
4
a Ethyl diazoacetate was added in one portion; yields were not determined.
Table 2. Asymmetric cyclopropanation of styrene and diazoacetate with 6 as the catalyst
Ph
1 mol% 6
CO2R
CO2R
+
+
N2CHCO2R
Ph
CH2Cl2
9
8
Entry
R
Yield (%)
Ratio (trans:cis)
Ee (%)
trans
cis
5a
6
7
8
9
Me
Et
i-Pr
t-Bu
(−)-Menthyl
(+)-Menthyl
85
88
88
75
66
76
85:15
90:10
95:5
88
96
90
86
58
85
56
83
63
54
44
4
97:3
95:5b
96:4b
10
a All reactions were carried out under the following conditions unless otherwise specified: styrene (5 mmol), diazoacetate (0.6 mmol, 0.5N in
CH2Cl2), catalyst 1 (6 mmol), CH2Cl2 (1 mL), 20–25°C, ca. 4 h for addition of diazoacetate then stirring for 4–8 h. Isolated yields. The cis/trans
ratios and ee’s were determined by Chiral GC column (beta dex 120, 30 m), the % ee’s were determined with the corresponding ethyl ester.
Absolute configuration: (1S,2S) for trans, (1S,2R) for cis.
b The ratios were determined by 1H NMR.
8–10). Ethyl diazoacetate turned out to be the best in
terms of yield and enantioselectivity although the trans/
cis ratio was lower than other sterically hindered esters.
rich, electron-poor, aromatic, and aliphatic olefins.
High ee’s (93–83%) were obtained for trans cyclopropa-
nation products. While enantioselectivities were com-
parable, yield for an electron-rich olefin was higher
than that for an electron-poor olefin since more carbene
dimerization products were formed in the latter case10
(entries 11 and 12). An aliphatic olefin also provided
We thus used ethyl diazoacetate as the carbene source
to react with olefin substrates. As shown in Table 3, Ru
complex 6 showed a broad substrate scope for electron-
Table 3. Results of cyclopropanation of olefins with ethyl diazoacetate catalyzed by 6
R1
R1
R2
CO2Et
+
N2CHCOOEt
R2
Entrya
Olefin
R1
R2
Yield (%)
Ratio (trans:cis)
Ee (%)
trans
cis
11
12
13
14
15
10
11
12
13
14
H
H
H
H
p-Cl-Ph
45
78
78
45
82
90:10
87:13
90:10
83:17
47:53
92
86
83
91
93
70
69
72
86
93
p-MeO-Ph
2-Naphthyl
n-C5H11
Ph
CH3
a Cyclopropanation of these olefins were carried out under the conditions used for entry 5.

3078
W. Tang et al. / Tetrahedron Letters 43 (2002) 3075–3078
high ee’s, although the yield was moderate (entry 13).
Good yield and excellent ee’s were also obtained for
a-methyl styrene (entry 14).
3. (a) Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S.-B.;
Itoh, K. J. Am. Chem. Soc. 1994, 116, 2223–2224; (b)
Nishiyama, H.; Itoh, Y.; Sugawara, Y.; Matsumoto, H.;
Aoki, K.; Itoh, K. Bull. Chem. Soc. Jpn. 1995, 68,
1247–1262.
4. (a) Uchida, T.; Irie, R.; Katsuki, T. Tetrahedron 2000, 56,
3501–3509; (b) Uchida, T.; Irie, R.; Katsuki, T. Synlett
1999, 1793–1795; (c) Uchida, T.; Irie, R.; Katsuki, T.
Synlett 1999, 1163–1165.
In conclusion, we have discovered a new and efficient
chiral ruthenium catalyst 6, which has been successfully
applied in catalytic asymmetric cyclopropanation. It is
noteworthy that high ee’s have been reached for trans
cyclopropanation products with the easily accessible
and cheap ethyl diazoacetate as the reagent and low
catalyst loading (1 mol%) has been achieved. Since
NOBIN can be easily prepared and resolved, our ruthe-
nium catalyst 6 is potentially practical for the synthesis
of a variety of chiral cyclopropane compounds. Further
studies are focused on structural modifications of the
ruthenium complex as well as its applications for other
asymmetric reactions and this progress will be reported
in due course.
5. Munslow, I. J.; Gillespie, K. M.; Deeth, R. J.; Scott, P.
Chem. Commun. 2001, 1638.
6. For the synthesis of NOBIN, see: (a) Smrcˇina, M.;
Lorenc, M.; Hanusˇ, V.; Kocˇovsky, P. Synlett 1991, 231;
(b) Smrcˇina, M.; Vyskocˇil, S.; Polivkova´, J.; Pola´kova´, J.;
Kocˇovsky`, P. Collect. Czech. Chem. Commun. 1996, 61,
1520–1524; (c) Ding, K.; Xu, Q.; Wang, Y.; Liu, J.; Yu,
Z.; Du, B.; Wu, Y.; Koshima, H.; Matsuura, T. Chem.
Commun. 1997, 693–694; (d) a more facile way for the
synthesis of NOBIN has been developed in our group
and will be reported soon. For the resolution of recemic
NOBIN, see: (a) Singer, R. A.; Shepard, M. S.; Carreira,
E. M. Tetrahedron 1998, 54, 7025–7032; (b) Ding, K.;
Wang, Y.; Yun, H.; Lin, J.; Wu, Y.; Terada, M.; Okubs,
Y.; Mikami, K. Chem. Eur. J. 1999, 5, 1734–1737.
7. Small impurity is the mono Schiff base product, which is
not removable via recrystallizations.
Acknowledgements
This work was supported by the National Institute of
Health. We thank Dr. A. Daniel Jones for his effort on
MS analysis.
1
8. Spectra data for 5: H NMR (CD2Cl2, 360 MHz) l 8.85
(d, 6.4 Hz, 2H), 7.94 (d, 8.1 Hz, 2H), 7.86 (d, 8.6 Hz,
4H), 7.77 (s, 2H), 7.73 (m, 1H), 7.48 (m, 8H), 7.38 (dt, 8.3
Hz, 1.2 Hz, 2H), 7.31 (dt, 6.8 Hz, 1.2 Hz, 2H), 7.21 (m,
6H), 7.19 (t, 6.5 Hz, 2H), 7.03 (t, 1H), 6.82 (m, 4H); 13C
NMR (CD2Cl2, 75 MHz) l 167.3, 162.32, 157.0, 151.7,
147.7, 136.9, 134.3, 133.6, 130.8, 130.6, 129.3, 129.2,
128.9, 128.4, 128.2, 128.1, 127.7, 127.6, 126.4, 125.7,
125.0, 124.7, 124.6, 124.5, 124.2, 122.9; MS (ESI) m/z 921
(M++1), 885 (M+−Cl), 849 (M+−2Cl). HRMS calcd for
RuC52N4H36O2Cl 885.1582, found: 885.1619.
References
1. For recent reviews, see: (a) Pfalz, A.; Lydone, K.; Mcker-
vey, M. A.; Charette, A. B.; Leel, H. In Comprehensive
Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer, 1999; pp. 513–603; (b)
Doyle, M. P.; Protopopova, M. Tetrahedron 1998, 54,
7919–7946; (c) Doyle, M. P.; Forbes, D. C. Chem. Rev.
1998, 98, 911–935.
1
9. Spectra data for 6: H NMR (CD2Cl2, 360 MHz) l 8.39
(d, 8.6 Hz, 2H), 8.08 (d, 8.9 Hz, 2H), 8.00 (d, 8.1 Hz,
2H), 7.92 (m, 4H), 7.81 (d, 8.8 Hz, 2H), 7.53 (t, 7.0 Hz,
2H), 7.39 (m, 4H), 7.29 (t, 7.3 Hz, 2H), 7.19 (dd, 8.4 Hz,
12.4 Hz, 4H), 7.10 (d, 8.4 Hz, 2H), 6.97 (t, 7.9 Hz, 1H),
6.86 (d, 7.3 Hz, 2H), 6.39 (s, 2H), 3.98 (s, 1H), 3.37 (s,
3H); 13C NMR (CD2Cl2, 75 MHz) l 166.1, 164.1, 151.6,
148.7, 136.8, 134.4, 133.8, 130.9, 130.4, 129.6, 129.3,
128.9, 128.2, 127.8, 127.3, 126.8, 125.8, 125.6, 125.3,
124.9, 124.5, 123.5, 121.7, 51.2; MS (ESI) m/z 888 (M++
CH3CN−CH3OH−Cl), 847 (M+−CH3OH−Cl). HRMS
calcd for RuC49N4H34O2Cl 847.1424, found: 847.1380.
10. Formation of fumarate and maleate as the carbene
dimerization product is a general phenomenon in metal
catalyzed cyclopropanation of olefins with diazoacetate.
2. Chiral copper catalyts: (a) Aratani, T. Pure Appl. Chem.
1985, 57, 1839; (b) Fritschi, H.; Letenegger, U.; Pfaltz, A.
Angew. Chem., Int. Ed. Engl. 1986, 25, 1005–1006; (c)
Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Foul, M.
M. J. Am. Chem. Soc. 1991, 113, 726–728; (d) Lowenthal,
R. E.; Abiko, A.; Masamune, S. Tetrahedron Lett. 1990,
31, 6005–6008. Chiral rhodium catalyst: (e) Doyle, M. P.;
Austin, R. E.; Bailey, A. S.; Dwyer, M. P.; Dyatkin, A.
B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.; Oalmann,
C. J.; Pieters, R. J.; Protopopora, M. N.; Raab, C. E.;
Roos, C. E.; Roos, G. H. P.; Zhou, Q.-L.; Martin, S. F.
J. Am. Chem. Soc. 1995, 117, 5763–5775; (f) Davies, H.
M. L.; Bruziniski, P. R.; Lake, D. H.; Kong, N.; Fall, M.
J. J. Am. Chem. Soc. 1996, 118, 6897.