Olefin cyclopropanation by a sequential atom-transfer radical addition and dechlorination in the presence of a ruthenium catalyst

Article abstract of DOI:10.1002/anie.200904278

Without diazo: The reductive coupling of olefins with dichloro compounds in the presence of a ruthenium catalyst and magnesium gives cyclopropanes in good yield (see scheme).

Full text of DOI:10.1002/anie.200904278

Angewandte
Chemie
DOI: 10.1002/anie.200904278
Synthetic Methods
Olefin Cyclopropanation by a Sequential Atom-Transfer Radical
Addition and Dechlorination in the Presence of a Ruthenium
Catalyst**
Katrin Thommes, Gregor Kiefer, Rosario Scopelliti, and Kay Severin*
Cyclopropanes can be found in a number of biologically
active compounds, and methods for the synthesis of this
smallest carbocycle have been investigated extensively.[1]
Most often, cyclopropanations are performed with Sim-
mons–Smith-type reagents or by transition metal catalyzed
reactions of olefins with diazo compounds.[1] Cyclopropanes
can also be synthesized by reductive coupling of 1,3-dihalogen
derivatives. Reagents, which can induce this transformation,
include metals such as Na,[2] Mg,[3] or Zn,[4] alkyllithium,[5] and
Grignard compounds,[6] and transition metal complexes,[7]
among others.[8] However, dehalogenation reactions are not
very popular for synthetic applications. A likely explanation
for the dominance of olefin cyclopropanations is the fact that
olefins are easier to access than 1,3-dihalides. Furthermore, it
is possible to control the stereochemistry of the products with
the help of chiral auxiliaries.[1b] Herein we describe a novel
one-pot procedure for the synthesis of substituted cyclo-
propanes. Olefins are reacted with 1,1’-dichlorides in a
ruthenium-catalyzed atom-transfer radical addition (ATRA)
process. The resulting 1,3-dichlorides are directly converted
into cyclopropanes by reductive coupling with magnesium
(Scheme 1). This method is applicable to a wide range of
substrates and the reactions can be performed in an inter- and
intramolecular fashion.
ATRA reaction of olefins with polyhalogenated com-
pounds.[10,11] Copper complexes have also been used widely
in this context.[12,13] One of the best procedures described so
far is based on the ruthenium(III) complex [Cp*RuCl2(PPh3)]
(1; Cp* = pentamethylcyclopentadienyl), which is employed
in conjunction with AIBN[14] (AIBN = azobis(isobutyroni-
trile)) or Mg.[15] The additives AIBN and Mg are used to
generate and regenerate the catalytically active ruthenium(II)
species by reduction of the ruthenium(III) complex.[16] This
novel procedure allows performing intermolecular ATRA
reactions as well as intramolecular atom-transfer radical
cyclization (ATRC) reactions with high efficiency. Since the
addition products are 1,3-dihalides, we were interested in
exploring the possibility of coupling ruthenium-catalyzed
ATRA and ATRC reactions with a dehalogenation step to
produce cyclopropanes.[17] There were indications that reac-
tion sequences of this kind can be realized. Baldovini et al.
have reported that the ATRC products of highly activated
dichloromalonamides and dichloromalonates can be con-
verted into cyclopropanes with stoichoimetric amounts of a
copper complex.[18] However, the method failed for less active
substrates. In a report about the crystal structure of 2-phenyl-
1-chlorocyclopropane-1-carbocyclic acid, it was mentioned
that the compound was obtained by a copper-induced ATRA
reaction at high temperature, but experimental details were
not given.[19]
As a test reaction we used the coupling of styrene with
ethyl dichloroacetate (Scheme 2). Screening of different
reactions conditions revealed that magnesium in combination
with THF can induce the cyclization step of the ATRA
product. The radical addition, however, was best performed in
a nonpolar organic solvent such as toluene. We therefore
decided to employ a one-pot, two-step procedure.[17] First,
ethyl dichloroacetate was coupled to styrene at 608C in
toluene using 1 mol% of the ruthenium catalyst 1 in
combination with Mg (40 equiv with respect to the styrene).
After six hours the toluene solution was cooled to 08C,
Scheme 1.
In 1973, it was reported that the complex [RuCl2(PPh3)3] is
able to catalyze the addition of CCl4 or CHCl3 to olefins
(“Kharasch reaction”).[9] Since then, numerous ruthenium
complexes have been tested for their ability to catalyze the
[*] K. Thommes, G. Kiefer, Dr. R. Scopelliti, Prof. K. Severin
Institut des Sciences et Ingꢀnierie Chimiques
ꢁcole Polytechnique Fꢀdꢀrale de Lausanne (EPFL)
1015 Lausanne (Switzerland)
Fax: (+41)21-693-9305
E-mail: kay.severin@epfl.ch
[**] This work was supported by the Swiss National Science Foundation
and by the EPFL.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904278.
Scheme 2.
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8115

Communications
diluted with THF, and the reaction proceeded for an addi-
For the reactions listed in Table 1, the ATRA step was
performed at slightly elevated temperature with reaction
times between 6 and 24 hours. The dechlorination step,
however, was very fast, and cooling to 08C turned out to
beneficial for some substrates (Table 1, entries 1–3, 8, and 10).
Previous studies about cyclopropanations by the reductive
coupling of 1,3-dihalides had focused on either iodides or
bromides, since chlorides are significantly less reactive.[4a,8a]
The successful coupling of the chlorinated ATRA products
under very mild reaction conditions was thus surprising. To
investigate the second step of the reaction in more detail,
dehalogenation reactions were performed with the isolated
ATRA product of chloroform and styrene as the model
compound. The reactions were carried out at room temper-
ature in pure THF with an excess of magnesium in the
presence and absence of the ruthenium catalyst 1. The
ruthenium complex was found to accelerate the dechlorina-
tion reactions substantially. With 1 mol% of the ruthenium
catalyst, the reaction was finished in less than two hours,
whereas in the absence of ruthenium it needed four hours to
go to completion (for details see the Supporting Information).
Furthermore, both reactions
tional hour. 2-Phenylcyclopropane-1-carboxylic acid ethyl
ester was then obtained as a mixture of isomers (cis/trans =
1:3.0) in good yield.
Encouraged by the results of the reaction between styrene
and ethyl dichloroacetate, we investigated the coupling of
other substrates. Under similar conditions as described above,
cyclopropanes were obtained for numerous chlorinated sub-
strates and olefins (Table 1). Styrene derivatives were suc-
cessfully reacted with ethyl dichloroacetate (Table 1,
entries 1–4), dichloroacetonitrile (Table 1, entries 5 and 6)
and chloroform (Table 1, entry 7) to give the corresponding
cyclopropanes as a mixture of cis/trans isomers. Cyclopropa-
necarboxamides can also be obtained by this methodology as
demonstrated by the reaction of styrene with a dichloroace-
tamide (Table 1, entry 8). Methylmethacrylate, a substrate
with a high tendency to form polymeric side products, and the
internal olefin cyclohexenylbenzene could both be reacted
with ethyl dichloroacetate to give the corresponding cyclo-
propanes in acceptable yields (Table 1, entries 9 and 10).
proceeded with a pronounced
induction period. It is well-
known that cross-coupling
Table 1: Sequential ATRA/dechlorination reactions catalyzed by complex 1 in the presence of Mg.[a]
Entry Olefin
Cl2HCR
Product
t1 T1 t2 T2 Yield cis/
[h] [8C] [h] [8C] [%][b] trans[c]
reactions,
which
involve
Grignard reagents, can be cat-
alyzed by iron(III) com-
plexes.[20] The catalytically
active species are assumed to
be low-valent iron complexes,
which are formed by reduction
of the iron(III) precursors by
the Grignard reagents. The
cyclization of the ATRA prod-
ucts should proceed via mag-
nesium–organic intermediates.
74
(82)
1
2
styrene
Cl2HCCO2Et
Cl2HCCO2Et
6
6
60
60
1
1
0
0
1:3.0
1:2.7
69
(80)
p-methoxystyrene
70
(79)
3
p-fluorostyrene
Cl2HCCO2Et
6
6
60
60
1
0
1:2.0
61
(70)
4
5
6
a-methylstyrene
styrene
Cl2HCCO2Et
Cl2HCCN
Cl2HCCN
1
2
2
25
25
25
1:3.3
1:2.8
1:2.4
70
(80)
À
It is conceivable that the C C
24 60
24 60
coupling reactions are directly
promoted by a ruthenium com-
plex in a low oxidation state (as
in the case of Fe), but an
indirect mode of action (e.g.,
activation of Mg) is plausible
as well.
65
(75)
a-methyl styrene
71
(80)
[d]
7
8
styrene
styrene
CHCl3
24 60
24 60
2
1
25
0
1:2.3
1:1.2
65
Cl2HCCONBn2
(72[e])
Next, we investigated the
synthesis of bicyclic cyclopro-
panes by one-pot ATRC/de-
chlorination reactions. Two dif-
ferent classes of substrates
were employed: trichlorinated
allylethers and di- and tri-
chlorinated N-allylacetamides.
Using 1–2 mol% of the ruthe-
nium catalyst 1, we were able
to isolate the cyclopropanes in
yields between 57 and 67%
(Table 2, entries 1–7). The cyc-
lization of the ethers [(2,2,2-
60
(67)
9
methylmethacrylate Cl2HCCO2Et
8
60
3
25
0
1:2.9
51
(62)
10[f] cyclohexenylbenzene Cl2HCCO2Et
48 60 0.5
1:12.6
[a] The reactions were performed in toluene with [olefin]=0.33m, [Cl2HCR]=0.33m, and [olefin]/[Mg]=1:40.
Ruthenium catalyst 1: 1 mol% relative to the substrates. After the time t1 at temperature T1,the reaction
mixture was diluted with 2.5 times the volume of THF an then stirred for the time t2 at temperature T2.
[b] Yield of isolated product; the values in brackets correspond to the yield of the product in the crude
reaction mixture as determined by GC/MS methods. [c] Determined by GC/MS methods, entry 8:
determined by NMR analysis. [d] [styrene]/[CHCl3]=1:2. [e] Yield of product in crude reaction mixture as
determined by NMR analysis. [f] The reaction was performed with 3 mol% Ru and [olefin]/[Cl2HCR]=1.5:1.
Bn=benzyl.
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Table 2: Sequential ATRC/dechlorination reactions catalyzed by complex 1 in the presence of Mg.[a]
When the corresponding tri-
chloroacetamides were subjected
to our reaction conditions, the
product was found to depend on
the nature of the substituents. For
N,N-diallyl-2,2,2-trichloroaceta-
mide, the expected chlorinated
Entry
Substrate
Product
[Ru]
[mol%]
t1
[h]
T1
[8C]
t2
[h]
T2
[8C]
Yield
[%][b]
1
2
3
1
2
1
3
2
4
60
60
60
1
1
25
25
25
67 (77)[c]
61 (74)
65 (80)
3-azabicyclo[3.1.0]hexan-2-one
7
was obtained as the main product
(Table 2, entry 6). However, the
cyclization of N-allyl-2,2,2-tri-
chloro-N-phenylacetamide
resulted in the formation of a more
complex product (Table 2, entry 7).
The structure of the latter was
established by NMR spectroscopy,
mass spectrometry, and crystallo-
graphic analysis (see the Support-
ing Information). It consists of the
dimer 8, in which two 3-phenyl-3-
azabicyclo[3.1.0]hexan-2-one frag-
ments are joined through the C1
carbon atom. The reaction
sequence had thus provided a com-
pletely dechlorinated product. The
dimer 8 was formed in a diastereo-
selective fashion as a racemic mix-
ture of the R,R- and the S,S-isomer,
as evidenced by the NMR data and
the crystallographic analysis. We
have not been able to detect the
meso isomer, but small amounts of
the monomeric bicycles 1-chloro-3-
phenyl-3-azabicyclo[3.1.0]hexan-2-
one and 3-phenyl-3-azabicyclo-
[3.1.0]hexan-2-one were observed
as side products (ca. 10% each). At
present, we have no explanation
for the difference in reactivity of
the N-allyl- (Table 2, entry 6) and
the N-phenyl-acetamide (Table 2,
entry 7). It is remarkable, however,
that a complex product such as 8
0.5
4
5
2
1
1
4
60
60
0.5
0.5
0.5
25
0
62 (72)[d]
63 (72)
6
7
1
1
2
2
60
60
0
57 (63)[d]
24
25
61
[a] The reactions were performed in toluene with [olefin]=0.16m and [olefin]/[Mg]=1:40. After the time
t1 at temperature T1, the reaction mixture was diluted with 2.5 times the volume of THF an then stirred
for the time t2 at temperature T2. [b] Yield of isolated product; the values in brackets correspond to the
yield of the product in the crude reaction mixture as determined by GC/MS methods. [c] The cis/trans=
1:11.7 was determined by GC/MS methods. [d] Yield of product in crude reaction mixture as determined
by NMR analysis.
trichloroethoxy) prop-1-enyl]benzene (Table 2, entry 1) and
(3-(2,2,2-trichloroethoxy)prop-1-en-2-yl)benzene (Table 2,
entry 2) gave 3-oxabicyclo[3.1.0]hexanes (2 and 3). Different
synthetic routes have been suggested for the preparation of 3-
oxabicyclo[3.1.0]hexanes.[21] Our method is interesting
because the starting materials are easily accessible and
because the chloro substituent in the product is a good
handle for additional functionalization.
Three different N-allyl-2,2-dichloroacetamides were suc-
cessfully cyclized to provide the corresponding 3-azabicyclo-
[3.1.0]hexan-2-one derivatives 4–6 (Table 2, entries 3–5).
There has been considerable interest in the synthesis of this
bicyclic lactam/cyclopropane framework.[22] Importantly,
3-azabicyclo[3.1.0]hexan-2-one is a precursor of cis-2-amino-
methylcyclopropanecarboxylic acid (CAMP), a pharmaco-
logically active analogue of g-amino butyric acid (GABA).[23]
can be obtained with high diastereoselectivity in a simple one-
pot reaction.
In summary, we have described a novel method for the
synthesis of substituted cyclopropanes by sequential ATRA/
dechlorination reactions. The one-pot procedure is applicable
to a variety of substrates, and the reactions can be performed
in an inter- or intramolecular fashion. The required ruthe-
nium catalyst is air-stable and its synthesis is facile.[24] The
yields for this new cyclopropanation reaction are lower than
for some of the optimized procedures described previously.[1]
Furthermore, it is not easy to envision an enantioselective
version. However, a key advantage of our methodology is the
fact that functionalized cyclopropanes can be obtained with-
out the utilization of potentially problematic diazo com-
pounds. Instead, stable and readily accessible chlorinated
compounds are employed. Future work will include studies
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Communications
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Experimental Section
General: The ruthenium catalyst 1 was prepared as described in the
literature.[24] The substrates were either commercially available or
they were prepared following published procedures (for details see
the Supporting Information). Mg powder (> 99%) was purchased
from Fluka. To activate its surface, it was agitated by a stirring bar
under an atmosphere of dry dinitrogen for five days before use. All
reactions were performed under an atmosphere of dry nitrogen. The
solvents and the commercially available substrates were distilled from
appropriate drying agents and stored under nitrogen before use.
General procedure for sequential ATRA or ATRC/dechlorina-
tion reactions: Mg powder (40 equiv) and toluene were added to a
flask containing the desired amount of catalyst 1. The olefin (1 equiv)
and the chlorinated substrate (1 equiv) were added ([substrates
ATRA] = 0.33m, [substrates ATRC] = 0.16m) and the mixture was
stirred at 608C. After the time t1, the solution was cooled to RT (or
cooled to 08C) and about 2.5 times the volume of THF was added to
the reaction mixture in one portion. For all entries of Table 1 and for
the entries 1–3 of Table 2: when the reaction was finished, n-hexane
was added and the mixture was filtered. The solvent was removed
under reduced pressure and the product was purified by flash
chromatography on silica gel. For the entries 3–7 of Table 2: when the
reaction was finished, H2O was added and the mixture was extracted
with CH2Cl2. The organic phase was washed with water and dried
over MgSO4. The solvent was removed under reduced pressure and
the products were purified by flash chromatography on silica gel. The
yields of the crude products were determined by GC/MS using a
Varian 3800 spectrometer coupled to a Varian 2200 mass spectrom-
eter. Mesitylene or 1,4-bis(trifluoromethyl)benzene was used as
internal standard.
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Received: July 31, 2009
Published online: September 25, 2009
Keywords: carbocycles · cyclopropanes · magnesium · radicals ·
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