An efficient and highly enantio- and diastereoselective cyclopropanation of olefins catalyzed by Schiff-base ruthenium(II) complexes

Article abstract of DOI:10.1002/1521-3773(20020816)41:16<2953::AID-ANIE2953>3.0.CO;2-2

Both electron-rich and electron-deficient olefins - such as styrene and methyl methacrylate - undergo efficient (yields > 90%) cyclopropanation with ethyl diazoacetate as the carbene source to give predominantly trans products with exceptionally high enantioselectivity when the (salen)Ru catalyst shown is used (see scheme).

Full text of DOI:10.1002/1521-3773(20020816)41:16<2953::AID-ANIE2953>3.0.CO;2-2

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that there are no highly blocked sequences along the copolymer chains. The
micellar nanospheres were prepared by dropwise addition of the various
blend solutions of MAF/PCL in DMF into water, withmoderate stirring.
The appearance of a bluish hue signals the formation of micelles. The
mixture was stirred for approximately 24 hat room temperature, and then
DMF was removed by dialysis withpure water, whichresulted in stable
homopolymer/copolymer micelles in water. The micellar structure was
locked by cross-linking the hydrophilic shell layer through condensation
reactions between the carboxylic acid groups of poly(methylacrylic acid)
(PMAA) and the amino groups of hexamethylenediamine in the presence
of 1-(3-dimethyl-aminopropyl)-3-ethylcarbdiimide methiodide, which acti-
vates the carboxylic acid at room temperature.[3a] The cross-linked product
was then dialyzed with distilled water for 3 days to remove the by-products
of the reaction. The success of the cross-linking was confirmed by the fact
that the resultant nanoparticles maintained their integrity upon switching
the medium from water to a solvent mixture containing a large proportion
of DMF. DLS (Malven Autosizer-4700) studies on the cross-linked particles
found that no particle aggregation had taken place, which meant that there
had been almost, zero interparticle cross-linking. For conducting biode-
gradation of the core, an appropriate amount of dust-free lipolase solution
in water (Novozymes Co.) and dilute aqueous NaOH solution was added
into the SCK nanoparticulate dispersion.[6] Typical reaction conditions:
MAF-3/PCL (1:1, w/w), 50% cross-linked, C ¼ 2.9 î 10À4 gmLÀ1, pH 8 11
at 258C. TEM imaging was performed on a Philips CM 120 electron
microscope at an accelerating voltage of 80 kV. The specimens were
prepared on copper grids coated witha thin carbon film.
An Efficient and Highly Enantio- and
Diastereoselective Cyclopropanation of Olefins
Catalyzed by Schiff-Base Ruthenium(ii)
Complexes**
Jason A. Miller, Wiechang Jin, and
SonBinhT. Nguyen*
Dedicated to Professor Robert H. Grubbs
on the occasion of his 60th Birthday
Compounds containing the cyclopropane fragment have
received considerable attention because of their frequent
occurrence in natural products and their importance as
3]
valuable synthetic intermediates.[1 Since the introduction
of chiral cyclopropanation catalysts by Nozaki et al.,[4]
Aratani et al.,[5] and Nakamura et al.,[6] transition-metal-
catalyzed asymmetric cyclopropanation has emerged as one
of the most efficient synthetic routes to the optically pure
cyclopropane fragment.[2,7] Perhaps the most difficult aspect
of these asymmetric cyclopropanations is the simultaneous
control of yield and regio-, diastereo-, and enantioselectivity
while maintaining functional group tolerance.[8,9] In cyclo-
15]
18]
propanation studies of chiral copper[10
and rhodium[16
Received: April 8, 2002 [Z19060]
complexes it was found that high enantioselectivities and high
diastereoselectivities usually do not go hand-in-hand unless
reactions were carried out in an intramolecular manner.
Further, in the case of intermolecular cyclopropanation, best
enantio- and diastereoselectivities are often only achieved
withlarge diazo esters.
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Y. An, Polymer 1999, 40, 4521; e) X. Yuan, H. Zhao, M. Jiang, Y. An,
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Since the early 1980s, a number of ruthenium complexes
have been shown to catalyze olefin cyclopropanation.[1] In
view of the advantages that ruthenium-based catalysts have
over copper- and rhodium-based catalysts in functional-group
tolerance and cost, respectively, the last decade has witnessed
an increase in the number of reports on ruthenium-based
cylopropanation catalysts, many of which are porphyrin-
21]
based.[19 Because of the well-known challenges associated
with porphyrin synthesis, especially when chiral porphyrins
are involved, non-porphyrin multidentate ligands have at-
tracted a lot of attention from investigators over the last few
years. In 1994, Nishiyama and co-workers employed a chiral
Ru pybox catalyst (pybox ¼ bis(oxazolinyl)pyridine) for the
cyclopropanation of styrene with tert-butyl diazoacetate
(tBDA) and menthyl diazoacetate (MDA) which resulted in
25]
high enantio- and trans-selectivity.[22
However, when the
smaller–and more common–diazo ester ethyl diazoacetate
(EDA) is employed in this reaction, selectivities are much
lower (see Table 1, entry 9). Recently, Katsuki and co-workers
[*] Prof. Dr. S. Nguyen, J. Miller, Dr. W. Jin
Department of Chemistry
Northwestern University
2145 Sheridan Road, Evanston, IL 60208-3113 (USA)
Fax : (þ 1)847-467-5123
[6] a) Z. Gan, J. Fung, X. Jiang, C. Wu, W. K. Kuliche, Polymer 1999, 40,
1961; b) Z. Gan, T. Jim, M. Li, Z. Yuer, S. Wang, C. Wu, Macro-
molecules 1999, 32, 590; c) J. C. Ha, S. Y. Kim, Y. M. Lee, J. Controlled
Release 1999, 62, 381; d) Y. Zhao, T. Hu, Z. Lu, S. G. Wang, C. Wu, J.
Polym. Sci. Part B: Polym. Phys. 1999, 37, 3288.
E-mail: stn@chem.northwestern.edu
[**] We thank the reviewers for their helpful comments. Support from the
DuPont Company and the Beckman, Dreyfus, and Packard Founda-
tions are gratefully acknowledged. S.T.N. is an Alfred P. Sloan Fellow.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
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Table 1. Asymmetric cyclopropanation of styrene withEDA catalyzed by complexes 1 5[a] in comparison to other catalysts. Bold-faced data indicate the best
values.
Entry
[Ru] cat./ref.
Diazo ester
t [h]
trans:cis
Yield [%][b]
trans (% ee[c]
)
cis (% ee[c]
)
1
2
3
4
5
6
7
8
(S,S)-1
(R,R)-1
(S,S)-2
(R,R)-2
(S,S)-3
(R,R)-3
(R)-4
(R,R)-5
Nishiyama[22]
Katsuki[39]
Zheng[34]
EDA
EDA
EDA
EDA
EDA
EDA
EDA
EDA
EDA[d]
tBDA
EDA
3
3
3
3
3
3
3
3
10.8:1
10.8:1
10.6:1
10.6:1
10.7:1
10.7:1
7.2:1
95
95
96
94
90
95
93
95
98 (1S,2S)
99 (1R,2R)
99 (1S,2S)
99 (1R,2R)
98 (1S,2S)
99 (1R,2R)
12 (1R,2R)
> 99 (1R,2R)
88 (1R,2R)
N/A
96 (1S,2R)
96 (1R,2S)
95 (1S,2R)
96 (1R,2S)
95 (1S,2R)
95 (1R,2S)
25 (1R,2S)
> 99 (1R,2S)
78 (1R,2S)
97 (1S,2R)
0
3.4:1
9
10
11
12 20
24, irradiation
14
11.5:1
1:13.3
1:1.9
69
45[e]
15[f]
13 (1R,2R)
[a] Reaction conditions: EDA (0.5 mmol), styrene (2.5 mmol), catalyst (0.005 mmol), CH2Cl2, 3 h. [b] GC yield with undecane as an internal standard.
[c] Determined by using Supelco b-DEX series chiral GC columns (see Supporting Information for method). Absolute configuration determined from
known standards. [d] Slow addition of diazo ester over 4 his required. [e] 1H NMR yield. [f] GC yield withdiethyl adipate as internal standard.
reported the use of a Ru(BINOL derived salcen) complex as
a catalyst in the photo-induced cyclopropanation of styrene
with tBDA (salcen ¼ trans-1,2-cyclohexanediamino-N,N’-bis-
(salicylidene)).[26] In spite of the high enantio- and cis-
selectivity reported, the reaction yields for Katsuki×s catalyst
were generally low (Table 1, entry 10). Further, owing to
photolytic conditions reaction times for Katsuki×s catalysts are
generally long and optimal selectivity is only reported for the
more bulky tBDA. Recently, Munslow and co-workers
the analytically pure chiral ruthenium complexes in 48 86%
yield. 1H and 13C NMR (and X-ray diffraction[31]) studies
revealed that these complexes contain two molecules of
pyridine axially bound to the metal center in a trans
coordination mode. Treatment of these pyridine complexes
withexcess PPh resulted in no reaction which implies that
3
pyridine binds tighter to the Ru center than PPh3.
Complexes 1 5 were employed in catalytic amounts
(1 mol%) for the cyclopropanation of styrene with EDA at
ambient conditions [Eq. (1)]. Diastereo- and enantioselectiv-
reported the use of nonplanar a-cis ruthenium biaryldiimine
[27]
complexes to cyclopropanate olefins withEDA.
They
reported good yields and diastereoselectivities and moderate
to good enantioselectivities, however, the substrate scope was
limited to styrene derivatives and tethered substrates and the
ligand synthesis is quite complicated. More recently, Tang and
co-workers have also reported a [Ru(pyridyldiimine)Cl2]
catalyst for the cyclopropanation of styrene with EDA.[28]
Herein, we report the high-yield syntheses of the chiral
Ru salen complexes 1 5 containing trans-oriented
pyridine ligands (H2salen ¼ N,N’-bis(salicylidene)ethylenedi-
amine).[29,30] These compounds are very efficient catalysts for
the asymmetric cyclopropanation of both electron-rich and
electron-deficient olefins withEDA to give predominantly
trans products withexceptionally ihghenantioselectivity.
EDA was chosen as the test case because it is the most
readily available diazoester and, because of its small size, one
of the most difficult carbene precursors to employ in an
enantioselective cyclopropanation reaction.
Ph
Ph
CO2Et
CO2Et
Ph
Ph
CO2Et
CO2Et
(1R,2R)
(1R,2S)
1 mol% [Ru]
N2CHCO2Et
(1)
+
+
(1S,2S)
(1S,2R)
trans
cis
ity results for these reactions are listed in Table 1 (entries 1
8). The presence of dimeric side products, such as diethyl
fumarate and maleate, was negligible (< 1%) for each
reaction. For the cyclohexane-based system, the trans/cis
ratio was found to be at least 10.6:1 in all cases, in stark
contrast to that observed for Katsuki×s Ru(BINOL derived
salcen) catalyst[26] where high cis selectivity is the norm.
Katsuki×s work (as well as current studies in our group) shows
that substitution at the 3,3’-postitions of the salen ligand plays
a large role in the diastereoselectivity of ruthenium(ii) salen
catalysts, in contrast to that observed for the isoelectronic
cobalt(iii) salen system.[32] The trans/cis selectivity for our
salen-type catalysts decreases when other backbones are used
which shows that the 3,3’-substituents are not the only factors
governing diastereoselectivity. Exceptionally high enantio-
meric excesses of cyclopropane products were found for both
trans and cis isomers (Table 1). These remarkable ee values
can be attributed to backbone substituents and the intrinsic
properties of the highly effective salen ligand structure, which
has also proven to be useful in other examples of asymmetric
catalysis.[33] Interestingly, changing the substituent groups at
the 5,5’-positions from H to Me to tBu has little effect on the
resulting product selectivity. Isolation of analytically pure
catalyst is critical in our catalyst system. Zheng and co-
workers have presumably generated the PPh3 analogue of 1 in
1: R = tBu
2: R = Me
3: R = H
4: R1 = H, R2 = Me
5: R1 = Ph, R2 = Ph
R1
N
R2
N
N
N
N
O
N
O
Ru
Ru
tBu
O
R
O
tBu
R
N
N
tBu
tBu
tBu
tBu
Complexes 1 5 were prepared from the reaction of the in
situ prepared dilithium salt of the ligand, Li2(salen), with
[{RuCl2(p-cymene)}2], followed by the addition of excess
pyridine at room temperature. Recrystallization of the dark-
red crude products from toluene/hexanes mixtures afforded
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situ but their cyclopropanation selectivities for styrene are
quite low (Table 1, entry 11).[34]
needed to be run at higher olefin concentrations to minimize
carbene dimer formation. MMA is the substrate that gives the
best diastereoselectivity (trans/cis ¼ 100) and also shows
opposite enantioselectivity from that for other olefins. These
selectivities for MMA are the best observed to date.
The high trans selectivities of our ruthenium(ii) salen
catalyst for the cyclopropanation of styrene can be rational-
ized by a ZINDO-minimized model structure calculation,
which suggests that the olefin approach to the metal carbene
intermediate (above the plane, as depicted in Figure 1) leads
to a trans geometry between the olefin×s substituent with
Work carried out in the Doyle[35,36] and Nakamura[6,37]
laboratories has shown that a,b-unsaturated carbonyl com-
pounds and nitriles can yield racemic cyclopropanes through
the decomposition of pyrazoline intermediates, which result
from the noncatalyzed 1,3-dipolar cycloaddition of olefins
withdiazoesters. Althoughpyrazoline formation was a com-
peting reaction in our ruthenium-catalyzed acrylonitrile
cyclopropanation (Table 2), the enantiomeric excesses of the
cyclopropane products are quite high which suggests that
noncatalyzed cyclopropane formation from pyrazoline de-
composition is only a minor pathway. In the case of MMA
cyclopropanation catalyzed by our ruthenium salen com-
plexes, no evidence of the pyrazoline or olefin side-product
formation normally associated withteh 1,3-cycloaddition
reaction[1] was observed and stereoselectivities are excellent.
Thus, the 1,3-dipolar cycloaddition pathway is unlikely under
our reaction conditions (dichloromethane, room tempera-
ture). Indeed, control reactions (0.5 mmol EDA, 2.5 mmol
olefin, no catalyst, 5 mL CH2Cl2, 3 h, room temperature) show
no evidence of pyrazoline formation when MMA was used.
We have also taken steps to eliminate the possibility that
pyrazoline adducts can be selectively decomposed to chiral
cyclopropanes by our catalyst. Methyl methacrylate and
acrylonitrile 2-pyrazoline adducts were separately synthe-
sized[36] and then subjected to our catalyst under our typical
cyclopropanation conditions. No tautomerization to 1-pyrazo-
lines, pyrazoline decomposition, cyclopropane formation, or
olefin side-product formation occurred. This leads us to
believe that 1,3-dipolar cycloaddition is not a significant
mechanistic pathway for our RuII salen-type catalysts.
Figure 1. A ZINDO-optimized model structure of styrene as it approaches
the putative (salen)Ru-EDA carbene intermediate. Left: a ball-and-stick
model of this structure without a trans axial ligand. Right: a top-view space-
filling model showing an optimal fit. A model structure with an additional
trans-py axial ligand is given in the Supporting Information.
respect to the carbene group. This calculation supports our
observations that substituents in the 5,5’-positions of the salen
ligand do not significantly affect either diastereo- or enantio-
selectivity owing to their remote locations: the 5,5’-substitu-
ents are simply too far away from the metal carbene to
influence its orientation. the 3,3’-substituents, however, are
close enoughto keep the singlet carbene locked in position
while the olefin approaches.
The substrate scope of our catalyst system is quite
remarkable and covers a whole range of conjugated, elec-
tron-rich, electron-poor, and aliphatic olefins with good
enantioselectivity (Table 2). Methyl methacrylate (MMA)
proves to be the most active substrate for our system:
absolutely no carbene dimer was produced when only a 5:1
olefin:EDA ratio was used. However, all other substrates
It is interesting to note that cyclopropanation of trans-
piperylene withthe nonsymmetrical catalyst ( R)-4 results in a
Table 2. Asymmetric cyclopropanation of other electron-rich and electron-deficient olefins with EDA catalyzed by complexes 1, 4, and 5.[a] Bold-faced data
indicate the best values.
Olefin
[Ru] cat.
trans:cis
Yield [%][b]
trans (% ee)[c]
cis (% ee)[c]
(R,R)-1
(R)-4
(R,R)-5
(R,R)-1
(R)-4
(R,R)-5
(R,R)-1
(R)-4
(R,R)-5
(R,R)-1
(R)-4
100:1
100:1
100:1
1.8:1
1.6:1
1.9:1
2.6:1
2.1:1
1.2:1
4.1:1
4.4:1
3.8:1
3.1:1
2.9:1
4.3:1
26
95
53
57[d]
93
97
26[e]
74
28
80
84
91
30
36
20
2 (1S,2S)
Not observable
Not observable
Not observable
65 (1R,2S)
44 (1S,2R)
90 (1R,2S)
39 (1R,2S)
38 (1R,2S)
62 (1R,2S)
78 (1R,2S)
30 (1R,2S)
67 (1R,2S)
18 (1R,2S)
26 (1R,2S)
56 (1R,2S)
95 (1S,2S)
91 (1S,2S)
72 (1R,2R)
39 (1S,2S)
89 (1R,2R)
40 (1R,2R)
15 (1R,2R)
58 (1R,2R)
69 (1R,2R)
24 (1R,2R)
68 (1R,2R)
90 (1R,2R)
49 (1R,2R)
74 (1R,2R)
(R,R)-5
(R,R)-1
(R)-4
(R,R)-5
[a] Reaction conditions: 0.5 mmol EDA, neat olefin (used to minimize EDA dimer formation) withthe exception of MMA (2.5 mmol olefin, 0.005 mmol
catalyst, CH2Cl2, 12 h). Reactions are over within 2 3 h. [b] GC yield using undecane as an internal standard, with the exception of ethyl vinyl ether and 1-
pentene where benzyl ether was used. [c] Determined by using Supelco b-DEX series chiral GC columns (see Supporting Information for method). Tentative
absolute configurations determined by chiral GC elution orders.[40] [d] Only the terminal olefin of piperylene was cyclopropanated. [e] Pyrazoline formation
was a competing reaction when acrylonitrile was cyclopropanated.[35]
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2001, 1638 1639.
reversal of enantioselectivity in comparison to the use of
(R,R)-3 and (R,R)-5. This phenomenon has not been observed
with any other olefin, including a variety of other conjugated
olefins and olefins of similar size.[38] The reasons for this
reversal of enantioselectivity are currently being investigated.
Although the cyclopropanation of the unactivated olefin
1-pentene withour catalysts affords quantitative EDA con-
version, carbene dimerization is a significant competitor to
cyclopropane production. Neither slow addition of the
reactants (botholefin and EDA solutions) nor cahnging
reaction conditions (temperature, solvent, and olefin concen-
trations) helped to reduce dimer formation. Nevertheless, the
catalyst solution remains active for long periods in the
presence of excess 1-pentene: successive addition of one
equivalent EDA per day over four days continues to generate
2-propyl cyclopropanecarboxylic acid ethyl ester at the same
rate and diastereoselectivity eachtime.
In summary, our ruthenium-based salen complexes con-
stitute an important addition to the rank of modern asym-
metric cycloproporation catalysts, as a result of their ease of
synthesis, high activity/selectivity, and broad applicability to a
wide range of electronically diverse terminal olefins.
Experimental Section
General procedures for the syntheses and characterizations of catalysts 1 5
and details of the calculation are available in the Supporting Information.
Also included are all chiral GC methods and information regarding the
characterization of cyclopropanes.
Preparation of complexes 1 5 (general procedure): Under an inert
atmosphere, a THF solution (15 mL) of the salen ligand (1.5 mmol) was
treated withlithium diisopropylamide (LDA; 2 mL of a 1.5 m solution of
the monotetrahydrofuran complex in cyclohexane, 3.0 mmol) at 08C. After
the addition was completed, the solution was allowed to warm up to room
temperature and stirred for 1 h. This mixture was then added dropwise to a
solution of [{RuCl2(p-cymene)}2] (460 mg, 0.75 mmol) and pyridine (1 mL)
in THF (15 mL) at 08C. The reaction mixture was allowed to stir overnight.
A dark-red solution was obtained, which was subsequently evaporated in
vacuo. The residue was extracted into toluene (30 mL), filtered through a
cannula, and evaporated under reduced pressure. Hexanes (20 mL) was
then added to the residue to precipitate a dark red solid, which was filtered
through a cannula and dried under vacuum. Further recrystallization with a
toluene/hexanes mixture affords analytically pure compounds.
[28] W. Tang, X. Hu, X. Zhang, Tetrahedron Lett. 2002, 43, 3075 3078.
[29] S. T. Nguyen, W. Jin, Abst. Pap. 218th ACS National Meeting (New
Orleans, LA), 1999, INOR-104.
[30] S. T. Nguyen, W. Jin, USA Patent Appl. 2000, 22 pp.
[31] E. J. Hennessy, W. J. Marshall, M. A. Scialdone, S. T. Nguyen,
unpublished data.
[32] T. Fukuda, T. Katsuki, Synlett 1995, 825 826.
[33] E. N. Jacobsen, W. Zhang, M. L. Guler, J. Am. Chen. Soc. 1991, 113,
6703 6704.
[34] Z. Zheng, X. Yao, M. Qiu, W. Lu, H. Chen, Tetrahedron: Asymmetry
2001, 12, 197 204.
[35] M. P. Doyle, R. L. Dorow, W. H. Tamblyn, J. Org. Chem. 1982, 47,
4059 4068.
[36] M. P. Doyle, M. R. Colsman, R. L. Dorow, J. Heterocycl. Chem. 1983,
20, 943 946.
[37] A. Nakamura, A. Konishi, Y. Tatsuno, S. Otsuka, J. Am. Chem. Soc.
1978, 100, 3443 3448.
General procedure for the asymmetric cyclopropanation of styrene with
EDA: A mixture of a chiral ruthenium salen catalyst (0.005 mmol) and the
olefin (2.5 mmol) in CH2Cl2 (1 mL) was placed in a 25-mL round-bottomed
flask under N2 in a glovebox. A CH2Cl2 solution (degassed three times) of
EDA (0.50 mmol in 2.5 mL total volume) and internal standard
(0.50 mmol) was slowly added through a gas-tight syringe over a period
of 23 min under N2. After the addition was complete the reaction mixture
was allowed to stir for 12 h at room temperature. The solution was then
passed through a short plug of silica gel to remove catalyst and washed with
CH2Cl2 (15 mL). Samples were then analyzed by GC.
Received: January 7, 2002
Revised: May 28, 2002 [Z18536]
[38] J. A. Miller, S. T. Nguyen, unpublished data.
[39] T. Uchida, R. Irie, T. Katsuki, Synlett 1999, 1793 1795.
[40] B. H. Hoff, T. Anthonsen, Chirality 1999, 11, 760 767.
[1] M. P. Doyle, M. A. McKervey, T. Ye, Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds, Wiley, New York, 1998.
2956
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