Highly cis-Selective cyclopropanations with ethyl diazoacetate using a novel Rh(I) catalyst with a chelating n-heterocyclic iminocarbene ligand

Article abstract of DOI:10.1021/ol802591j

(Chemical Equation Presented) A structurally characterized Rh(I) iminocarbene complex (N,C)Rh(CO)Cl is activated with AgOTf to act as a highly cis-selective catalyst for the cyclopropanation of substituted styrenes and other alkenes with ethyl diazoacetate (11 examples, 10-99% yield, up to >99% cis-selectivity).

Full text of DOI:10.1021/ol802591j

ORGANIC
LETTERS
2009
Vol. 11, No. 3
547-550
Highly cis-Selective Cyclopropanations
with Ethyl Diazoacetate Using a Novel
Rh(I) Catalyst with a Chelating
N-Heterocyclic Iminocarbene Ligand
Marianne Lenes Rosenberg,† Alexander Krivokapic,† and Mats Tilset*,‡
Department of Chemistry, UniVersity of Oslo, P.O. Box 1033 Blindern, N-0315 Oslo, Norway,
and Centre for Theoretical and Computational Chemistry, Department of Chemistry, UniVersity
of Oslo, P.O. Box 1033 Blindern, N-0315 Oslo, Norway
mats.tilset@kjemi.uio.no
Received November 10, 2008
ABSTRACT
A structurally characterized Rh(I) iminocarbene complex (N,C)Rh(CO)Cl is activated with AgOTf to act as a highly cis-selective catalyst for the
cyclopropanation of substituted styrenes and other alkenes with ethyl diazoacetate (11 examples, 10-99% yield, up to >99% cis-selectivity).
Cyclopropanes are important substructures in many biologically
active compounds.1-3 Metal-catalyzed cyclopropanation reac-
tions are well-known, and the most common catalytic method
of obtaining cyclopropanes involves transfer of a carbene
moiety from a diazocarbonyl compound to an olefin. In such
a reaction, two new stereogenic centers are formed, leading
to two diastereomeric products.
There are, however, only few reports on cis-selective
catalysts for this type of reaction.13-19 Among these is a
Cu(I) homoscorpionate catalyst that gives very good yields
and high cis-selectivity in the reaction between ethyl diaz-
oacetate and styrene.20 Ru21-25 and Co-salen26 complexes
have been reported to display high cis-selectivities with ethyl
diazoacetate. Recently, Co27 and Ir-salen28 complexes give
One challenge in intermolecular cyclopropanation reactions
can be to control which diastereomer is formed, especially
with commonly used carbonyl diazo compounds like the
commercially available ethyl diazoacetate. Many catalysts
have been developed that are selective for formation of the
thermodynamically favored trans-isomer.4-12
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† Department of Chemistry.
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M.; Masson, S. Tetrahedron: Asymmetry 2004, 15, 2569–2573.
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Lett. 2004, 45, 5649–5652.
‡ Centre for Theoretical and Computational Chemistry.
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for Organic Synthesis with Diazo Compounds: From Cyclopropanes to
Ylides; Wiley: New York, 1998
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Ed.; Springer: Berlin, Germany, 2000
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10.1021/ol802591j CCC: $40.75
Published on Web 12/24/2008
2009 American Chemical Society

Scheme 1
Figure 1. Iminocarbene ligands and complexes previously reported.
very high cis-selectivities with tert-butyl diazoace-
tate.
Among the Rh-based catalysts that are reported to be
useful for cyclopropanation reactions, there are a few that
give good cis-selectivities but rather low yields.29-33 We
here report the synthesis of a novel Rh(I) complex 5 with a
chelating N-heterocyclic iminocarbene ligand and the use
of this complex in cyclopropanation reactions.
Arduengo’s report on stable N-heterocyclic carbenes
(NHC’s)34,35 triggered the use of such species as ligands for
organometallic complexes. NHC-metal complexes are ex-
cellent catalysts for a wide range of chemical transforma-
tions.36-38 We have previously reported the synthesis of five-
and six-membered ring chelate complexes of Pd and Pt with
N-heterocyclic iminocarbene ligands of the types shown in
Figure 1.39-41
The related Rh(I) complex 5 was synthesized as shown
in Scheme 1. Iminoimidazolium salt 4 was synthesized in
good yields by the previously reported method.42
(13) Alexander, K.; Cook, S.; Gibson, C. L. Tetrahedron Lett. 2000,
The new Rh(I) complex 5 was obtained by reacting the
imidazolium salt 4 with commercially available Rh(acac)-
(CO)2, as described by Gade and co-workers for a related
NHC-oxazole Rh(I) complex.43 The 13C NMR spectrum of
5 exhibited a characteristic doublet for the carbene carbon
at δ 185.9 with J(103Rh-13C) ) 58 Hz. The IR νCdN
absorption of the imine was lowered by 54 cm-1 compared
to that of 4. These data strongly suggest that the iminocarbene
ligand has formed a κ2(C,N) chelate at Rh. This was verified
by an X-ray structure analysis of 5 (Figure 2).
Some Au and Cu complexes with NHC ligands show good
reactivity in cyclopropanation reactions.44,45 In view of the
fact that certain Rh complexes also catalyze such reac-
tions,29-33 we decided to subject our novel Rh(I) complex
5 to cyclopropanation conditions.
41, 7135–7138
.
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The reaction between ethyl diazoacetate (EDA) and styrene
was chosen as the initial test system (Table 1). The EDA
was added in one portion without sign of carbene dimeriza-
tion under cyclopropanation conditions. When 5 was mixed
with EDA and styrene in dichloromethane, essentially no
reaction was observed. Activation of 5 with silver triflate
T. Angew. Chem., Int. Ed. 2007, 46, 3889–3891
.
(29) Eagle, C. T.; Farrar, D.; Holder, G. N.; Hatley, M. L.; Humphrey,
S. L.; Olson, E. V.; Quintos, M.; Sadighi, J.; Wideman, T. Tetrahedron
Lett. 2003, 44, 2593–2595
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548
Org. Lett., Vol. 11, No. 3, 2009

Scheme 2
Table 2. Cyclopropanation of Different Alkenes to Examine the
Scope of the Catalysta
Figure 2. ORTEP drawing of 5 (hydrogens omitted for clarity,
entry
alkene
yieldb (%)
cis:transc
ellipsoids at 50% probability). Selected bond lengths (Å) and angles
(deg): Rh-N(1), 2.131(2); Rh-Cl, 2.3665(6); Rh-C(1), 1.953(2);
Rh-C(20), 1.813(3); C(5)-N(1), 1.293(3); C(5)-N(2), 1.386(3);
C(1)-Rh-C(20), 97.39(11); C(20)-Rh-Cl, 90.38(8); Cl-Rh-N(1),
93.40(6); N(1)-Rh-C(1), 78.53(9).
1
styrene
98
99
99
94
98
98
36
91
60
38
10
0
>99:1
>99:1
>99:1
>99:1
98:2
99:1
96:4
79:21
78:22
66:44
-
2
3
4
5
p-methoxystyrene
p-chlorostyrene
1-vinylnaphthalene
indene
6
7
8
9
10
11
12
13
cyclopentene
cyclohexene
Table 1. Cyclopropanation of Styrene with Ethyl Diazoacetate
1,4-cyclohexadiene
1-octene
R-methylstyrene
1,1-diphenylethene
trans-ꢀ-methylstyrene
cis-stilbene
under Different Conditionsa
mol
equiv
mol %
yield %b
entry % 5 styrene AgOTf T/°C time/h (cis:trans)c
-
-
1
2
3
4
5
6
7
8
9
0
10
10
10
10
1
5
20
20
0
16
48
48
3
19
24
2
n.r.
0
1
0
trace
a Reaction conditions: 0.050 mmol 5, 0.050 mmol AgOTf, 5.0 mmol
alkene, 1.00 mmol EDA in 20 mL of dichloromethane under an Ar
atmosphere at 0 °C. See Supporting Information for further details. b Isolated
yield based on EDA limiting reagent. c Determined by 1H NMR and GLC.
1
1
50 (92:8)
89 (94:6)
21 (75:25)
47 (95:5)
98 (>99:1)
96 (92:8)
98 (>99:1)
2.5
5
2.5
5
0
20
0
0
20
0
5
2.5
5
5
5
10
10
5
5
5
3
2
5
5
with 5 mol % of 5 and AgOTf and a 5-fold excess of alkene
at 0 °C. The catalyst exhibits excellent reactivity and
selectivity with p-substituted styrenes and 1-vinyl naphtha-
lene (entries 1-4).
a Reaction conditions: 1.00 mmol EDA and given quantities of 5, AgOTf,
and styrene in 20 mL of dichloromethane. Number of equiv of styrene,
mol % 5, and mol % AgOTf refer to molar quantity of EDA used. b Isolated
c
1
yield. cis:trans ratio determined by H NMR and GLC.
Some cyclic and aliphatic alkenes were also tested. The
catalyst displays remarkably high reactivity and selectivity
with cyclopentene, indene, and cyclohexene (Table 1, entries
5-7). To the best of our knowledge, these are the highest
cis-selectivities that have ever been reported with these
alkenes in reactions with ethyl diazoacetate.
The reaction with 1,4-cyclohexadiene forms cyclopropanes
in good yield with moderate diastereoselectivity (entry 8).
No C-H insertion products were seen in this experiment
despite the fact that cyclohexadiene is a good substrate for
Rh-mediated carbene insertion into the allylic C-H bonds.46
With 1-octene (entry 9), the selectivity and the reactivity
drops somewhat, although a good cis-selectivity still persists.
With disubstituted alkenes, the yields are lower, and the
diastereoselectivity is poorer (Table 1, entries 10-13).
During these reactions, formal carbene dimerization is
observed. These results suggest that the catalyst is quite
sensitive to steric hindrance at the alkene.
(AgOTf) in dichloromethane at room temperature for 20 min
before addition of styrene and EDA gave the cis- and trans-
cyclopropanes 6 and 7 in 96% isolated yield with a high
diastereomeric ratio, 92:8, in favor of the cis-isomer 6. A
control experiment in which silver triflate (but no 5) was
added resulted in no decomposition of the diazo compound,
no carbene dimerization, and no cyclopropanation. Our Rh
complex 5 is therefore required for the cis-selective cyclo-
propanation of styrene. We surmise that the role of the
AgOTf activation is to generate a cationic species with a
vacant coordination site, which is responsible for the catalytic
action. Alternative activation methods are under investigation.
The highest cis-selectivities and yields were achieved when
the reaction temperature was lowered to 0 °C. The yield was
now 98%, and the diastereomeric ratio was >99:1 in favor
of the cis-isomer (Scheme 2). This is among the highest cis-
selectivities that have ever been reported in such a reaction.
The scope of the catalytic reaction was explored with a
range of alkenes (Table 2). All reactions were conducted
(46) Muller, P.; Tohill, S. Tetrahedron 2000, 56, 1725–1731.
Org. Lett., Vol. 11, No. 3, 2009
549

In summary, we have synthesized a novel Rh(I) complex
bearing a chelating N-heterocyclic iminocarbene ligand. This
complex gives excellent yields and remarkably high cis-
diastereoselectivities in cyclopropanation reactions between
styrene and ethyl diazoacetate. The catalyst gives similarly
excellent to good results with monosubstituted aromatic
alkenes and cyclic alkenes. The catalytic system is under
continuing investigation in our laboratories, and we hope that
mechanistic studies will shed light on the mode of the
catalytic action which in turn may lead to even better and
more selective catalysts.
Acknowledgment. We acknowledge generous financial
support from the Norwegian Research Council (NFR).
Supporting Information Available: Characterization data
1
1
and H NMR of cyclopropanes, characterization and H
NMR, 13C NMR, COSY, and NOESY spectra of Rh complex
5, crystal data for 5, and structural data in cif format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL802591J
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Org. Lett., Vol. 11, No. 3, 2009