Olefin cyclopropanations via sequential atom transfer radical addition-dechlorination reactions

Article abstract of DOI:10.2533/chimia.2010.188

In organic synthesis, cyclopropanation reactions are often performed with Simmons-Smith-type reagents or by transition metal catalyzed reactions of olefins with diazo compounds. A novel method for the synthesis of substituted cyclopropanes is described that is based on a two-step reaction sequence. Olefins are reacted with 1,1'-dichlorides in a Ru-catalyzed atom transfer radical addition (ATRA) process and the resulting 1,3-dichlorides are directly converted into cyclopropanes by reductive coupling with magnesium. This one-pot procedure is applicable to a variety of substrates and can be performed in an inter- or intramolecular fashion. Schweizerische Chemische Gesellschaft.

Full text of DOI:10.2533/chimia.2010.188

188ꢀ CHIMIAꢀ2010,ꢀ64,ꢀNo.ꢀ3ꢀ
doi:10.2533/chimia.2010.188ꢀꢀ
Laureates: awards and Honors, sCs FaLL Meeting 2009
Chimiaꢀ64ꢀ(2010)ꢀ188–190ꢀ ©ꢀSchweizerischeꢀChemischeꢀGesellschaft
Olefin Cyclopropanations via Sequential
Atom Transfer Radical
Addition-Dechlorination Reactions
KatrinꢀThommes§*ꢀandꢀKayꢀSeverin
§SCS-DSMꢀNutritionalꢀProductsꢀAwardꢀWinnerꢀ(PosterꢀPresentation)
Abstract: Inꢀorganicꢀsynthesis,ꢀcyclopropanationꢀreactionsꢀareꢀoftenꢀperformedꢀwithꢀSimmons–Smith-typeꢀre-
agentsꢀ orꢀ byꢀ transitionꢀ metalꢀ catalyzedꢀ reactionsꢀ ofꢀ olefinsꢀ withꢀ diazoꢀ compounds.ꢀ Aꢀ novelꢀ methodꢀ forꢀ theꢀ
synthesisꢀofꢀsubstitutedꢀcyclopropanesꢀisꢀdescribedꢀthatꢀisꢀbasedꢀonꢀaꢀtwo-stepꢀreactionꢀsequence.ꢀOlefinsꢀareꢀ
reactedꢀwithꢀ1,1’-dichloridesꢀinꢀaꢀRu-catalyzedꢀatomꢀtransferꢀradicalꢀadditionꢀ(ATRA)ꢀprocessꢀandꢀtheꢀresultingꢀ
1,3-dichloridesꢀareꢀdirectlyꢀconvertedꢀintoꢀcyclopropanesꢀbyꢀreductiveꢀcouplingꢀwithꢀmagnesium.ꢀThisꢀone-potꢀ
procedureꢀisꢀapplicableꢀtoꢀaꢀvarietyꢀofꢀsubstratesꢀandꢀcanꢀbeꢀperformedꢀinꢀanꢀinter-ꢀorꢀintramolecularꢀfashion.
Keywords: Carbocyclesꢀ·ꢀCyclopropanesꢀ·ꢀMagnesiumꢀ·ꢀRadicalsꢀ·ꢀRuthenium
[15]
Introduction
were needed. Recently it was reported that PPh3
is well suited for difficult atom
the lifetime of the catalyst could be dras- transfer radical reactions. The addition
In the 1940s, Kharasch and co-workers tically improved by using a co-catalyst, of dichlorinated substrates to olefins or
discovered that halocarbons, such as CCl4, which acts as a reducing agent to regen- intramolecular ATRC reactions are per-
could be added to olefins through a radi- erate the active species.[7] One of the best formed with very good yields. The ad-
cal chain process.[1] Three decades later, systems described so far is the air-stable dition products, 1,3-dichlorides, were
the scope of the reaction was expanded half-sandwich complex [RuCl2Cp*(PPh3)] promising candidates for a sequential di-
by the discovery that the ruthenium com- (1) that is employed in conjunction with chlorination step.
plex [RuCl2(PPh3)3] is able to act as an AIBN[7d] or Mg[7b] as the co-catalyst. The
Screening of different reactions con-
efficient catalyst for this reaction.[2] Over role of the co-catalyst is the activation of ditions revealed that Mg in combination
the past years, several catalysts with im- the RuIII catalyst by reduction to a RuII with THF can induce a cyclization of the
proved catalytic performances have been complex, and the prevention of an accu- ATRA product of styrene and ethyl dichlo-
developed and meanwhile many transition mulation of RuIII complexes due to termi- roacetate. As it was found that the radical
metal complexes are known to promote in- nation reactions of carbon-centered radi- addition was best performed in a non-polar
ter- and intramolecular ATRA reactions.[3] cals.[8] This method allows intermolecular organic solvent such as toluene, a one-pot,
The highest activities are typically found ATRA reactions and intramolecular atom two-step reaction was employed (Scheme
for copper[4] and ruthenium[5] catalysts and transfer radical cyclization (ATRC) reac- 1). TheATRA reaction was first performed
interesting applications have been reported tions to be performed with high efficiency. in toluene and the mixture was then diluted
in organic synthesis.[6] Despite their high The addition products are 1,3-dihalides. with THF. This procedure gave 2-phenyl-
activities, a main disadvantage from a It had been reported that in the presence cyclopropane-1-carboxylic acid ethyl ester
practical point of view remained the cata- of various metals, such as Na,[9] Mg,[10] in good yields.
lyst stability; hence high catalyst loadings Zn,[11] Grignard compounds,[12] or transi-
A similar procedure was successfully
tion metal complexes,[13] cyclopropanes used for numerous chlorinated substrates
can be obtained by reductive coupling of and olefins. Styrene derivatives were re-
1,3-dihalogen derivatives. We were thus acted with ethyl dichloroacetate, dichlo-
interested to explore the possibility to roacetonitrile, and chloroform to give the
combine Ru-catalyzed ATRA and ATRC corresponding cyclopropanes as a mixture
reactions with a dehalogenation step to of cis-trans isomers (Scheme 2). Cyclo-
produce cyclopropanes. Our preliminary propanecarboxamides can also be obtained
results, which were recently published,[14] by this method as shown by the reaction
are summarized below.
of styrene with a dichloroacetamide. More
difficult substrates like methylmethacry-
late, which shows a high tendency to form
polymeric side products, and the internal
olefin cyclohexenylbenzene could be cou-
pled to ethyl dichloroacetate to give the
Sequential ATRA/ATRC-
Dechlorination Reactions
*Correspondence: K. Thommes
Institut des Sciences et Ingénierie Chimiques
École Polytechnique Fédérale de Lausanne (EPFL)
CH-1015 Lausanne
Tel.: +41 21 693 9313
Fax: +41 21 693 9305
The catalytic system based on a com- corresponding cyclopropanes in accept-
bination of magnesium and the ruthenium able yields (Scheme 2).
catalyst 1, which is air-stable and can be
From the synthetic point of view, intra-
easily synthesized from [Cp*RuCl]2 and molecular atom transfer reactions are very
E-mail: katrin.thommes@epfl.ch

Laureates: awards and Honors, sCs FaLL Meeting 2009ꢀ
CHIMIAꢀ2010,ꢀ64,ꢀNo.ꢀ3ꢀ 189
2-aminomethylcyclopropanecarboxylic
acid (CAMP).[17]
1. ATRA
CO2Et
2. Dechlorination
Cl
Cl
[1] + Mg, toluene
In most cases the dechlorination step
was very fast. This was surprising since
1,3-dichlorides are significantly less reac-
tive than 1,3-diiodides or 1,3-dibromides.
If the reaction was performed with the
isolated ATRA product of chloroform
and styrene as a model compound, the
Ru complex was found to accelerate the
dechlorination reaction substantially, and
an induction period was observed. More
detailed mechanistic studies are currently
being pursued in our laboratory.
Ph
THF
+
Ph
CO2Et
Cl2HCCO2Et
Ph
Ru
Cl
Ph3P
Cl
1
Schemeꢀ1.ꢀOne-potꢀsequentialꢀATRA-dechlorinationꢀreactionꢀofꢀstyreneꢀandꢀethylꢀdichloroacetate.
Conclusion
R2
1. 1 mol% [1] + Mg, toluene
A novel method for the synthesis of sub-
stituted cyclopropanes has been described.
Olefins are reacted with 1,1’-dichlorides in a
Ru-catalyzed atom transfer radical addition
process and the resulting 1,3-dichlorides are
directly converted into cyclopropanes by
reductive coupling with magnesium. This
one-pot reaction is applicable to a variety
of substrates and can be performed in an
inter- or intramolecular fashion. The cyclo-
propanation of ATRC products provides a
convenient method to build up bicyclic sys-
tems. The method has the advantage that the
starting materials are readily accessible and
that the utilization of potentially problematic
diazo compounds is avoided. Furthermore,
the Ru-catalyst is air-stable, easy to synthe-
size and the co-catalyst magnesium is cheap
and non-toxic.
2. THF
Cl2HCR2
R1
+
R1
CN
CO2Et
Ph
CONBn2
CO2Et
Cl
Ph
Ph
Ph
Ph
EtO2C
MeO2C
51%
51 %
60 %
60%
74%
74 %
71%
71 %
65%
65 %
70 %
70%
(isolated yields)
Schemeꢀ2.ꢀSelectedꢀproductsꢀforꢀATRA-dechlorinationꢀreactionsꢀcatalyzedꢀbyꢀcomplexꢀ1ꢀinꢀtheꢀ
presenceꢀofꢀMg.
interesting. The synthetic method outlined routes have been suggested for this struc-
above also allows the synthesis of bicyclic tural motif,[16] the method is interesting
systems in a one-pot reaction. Two dif- because the starting materials are easily ac-
ferent classes of substrates, trichlorinated cessible and because the chloro substituent
allylethers and di- and trichlorinated N- in the product can be used for further func-
allylacetamides, were employed and the tionalisation.
Acknowledgments
corresponding cyclopropanes could be
isolated in respectable yields.
Different
N-allyl-2,2-dichloroacet-
This work was supported by the Swiss
National Science Foundation and by the EPFL.
We thank Gregor Kiefer for his help with the
substrate synthesis and Rosario Scopelliti for
the crystallographic analysis.
amides were successfully cyclized to give
3-Oxabicyclo[3.1.0]hexanes were ob- the corresponding 3-azabicyclo[3.1.0]
tained by cyclization of [(2,2,2-trichloro- hexan-2-one derivatives (Scheme 4). This
ethoxy)prop-1-enyl]benzeneor(3-(2,2,2-tri- bicyclic lactam-cyclopropane framework
chloroethoxy)prop-1-en-2-yl)benzene has been of interest, because 3-azabicyc-
(Scheme 3). Although different synthetic lo[3.1.0]hexan-2-one is a precursor of cis-
Received: January 15, 2010
R1
1. 1-2 mol% [1] + Mg, toluene
O
Ph
2. THF
Ph
N
CR1Cl2
O
N
1. 1 mol% [1] + Mg, toluene
Cl
R2
2. THF
R2
CCl3
O
O
Cl
67%
67 %
O
O
O
O
N
N
N
N
Ph
Bn
1. 2 mol% [1] + Mg, toluene
Ph
Cl
Ph
CCl3 2. THF
65%
65 %
62%
62 %
63%
63 %
57%
57 %
O
O
61%
61 %
(isolated yields)
Schemeꢀ3.ꢀSequentialꢀATRC-dechlorinationꢀreactionsꢀofꢀtrichlorinatedꢀ
allylethers.
Schemeꢀ4.ꢀSequentialꢀATRC-dechlorinationꢀreactionsꢀofꢀdi-ꢀandꢀ
trichlorinatedꢀN-allylacetamides.

190ꢀ CHIMIAꢀ2010,ꢀ64,ꢀNo.ꢀ3ꢀ
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