An Inexpensive and Recyclable Silver-Foil Catalyst for the Cyclopropanation of Alkenes with Diazoacetates under Mechanochemical Conditions

Article abstract of DOI:10.1002/anie.201504236

The diastereoselective cyclopropanation of various alkenes with diazoacetate derivatives can be achieved under mechanochemical conditions using metallic silver foil and a stainless-steel vial and ball system. This solvent-free method displays analogous reactivity and selectivity to solution-phase reactions without the need for slow diazoacetate addition or an inert atmosphere. The heterogeneous silver-foil catalyst system is easily recyclable without any appreciable loss of activity or selectivity being observed. The cyclopropanation products were obtained with excellent diastereoselectivities (up to 98:2 d.r.) and in high yields (up to 96 %).

Full text of DOI:10.1002/anie.201504236

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Angewandte
Communications
International Edition: DOI: 10.1002/anie.201504236
German Edition: DOI: 10.1002/ange.201504236
Solid-Phase Synthesis
An Inexpensive and Recyclable Silver-Foil Catalyst for the
Cyclopropanation of Alkenes with Diazoacetates under
Mechanochemical Conditions
Longrui Chen, Mark O. Bovee, Betsegaw E. Lemma, Kimberlee S. M. Keithley, Sara L. Pilson,
Michael G. Coleman,* and James Mack*
Abstract: The diastereoselective cyclopropanation of various
alkenes with diazoacetate derivatives can be achieved under
mechanochemical conditions using metallic silver foil and
a stainless-steel vial and ball system. This solvent-free method
displays analogous reactivity and selectivity to solution-phase
reactions without the need for slow diazoacetate addition or an
inert atmosphere. The heterogeneous silver-foil catalyst system
is easily recyclable without any appreciable loss of activity or
selectivity being observed. The cyclopropanation products
were obtained with excellent diastereoselectivities (up to 98:2
d.r.) and in high yields (up to 96%).
support into the product mixture, and the support must be
continually charged with additional catalyst, which consti-
tutes an additional expense to the operation costs.[5] Alter-
natively, replacing precious-metal catalysts with more earth-
abundant materials would have many wide-ranging benefits
for developing sustainable processes. Towards this goal,
Pericàs and co-workers have developed a polystyrene-sup-
ported tris(triazolyl) methyl copper(I) complex for carbene
transfer reactions of ethyl diazoacetate to a wide range of
organic compounds both in batch and in continuous-flow
setups.[6] More recently, Jones, Davies, and co-workers also
developed a flow reactor system for highly enantioselective
À
T
he transition-metal-catalyzed decomposition of diazoace-
C H insertion reactions with immobilized chiral dirhodium
tates has been used in various synthetic strategies to afford
natural products and other biologically active compounds,
many requiring high enantioselectivity.[1] The catalytic inter-
molecular [2+1] cyclopropanation of alkenes in the presence
of diazoacetates is a well-studied transformation that is often
used as a baseline reaction for testing the activity and
selectivity of newly developed catalysts.[2] Whereas several
transition-metal salts have been shown to be catalytically
active for the cyclopropanation of alkenes in the presence of
carbene precursors, dirhodium(II) salts are widely recognized
as the benchmark catalysts for these transformations as they
enable the cyclopropanation of a wide range of substrates
with high chemo-, regio-, and stereoselectivity.[3] At the same
time, a significant financial cost is incurred by these precious-
metal catalysts. To alleviate some of the economic concerns
associated with homogeneous catalysts, several reports have
sought to immobilize them on a solid support to render the
catalysts recoverable and recyclable for future use.[4] Still,
multistep ligand syntheses and the cost of the solid support
place an additional burden on yielding a higher catalytic
activity (e.g., improved turnover numbers and frequencies) to
recover the initial cost of investment. Furthermore, over the
catalyst lifetime, rhodium metal is leached from the solid
salts.[7]
Transition-metal-catalyzed reactions under mechano-
chemical conditions have been shown to have many advan-
tages over traditional solution-based methods.[8] Furthermore,
many research groups have successfully carried out mecha-
nochemical reactions on the multikilogram scale.[9] It has been
shown that the milling reaction vessel can exert a heteroge-
neous catalytic influence on the mechanochemical reaction.[10]
For the past few years, our research group has been able to
conduct copper-catalyzed reactions simply by using a copper
reaction vessel as the heterogeneous surface for the catalyti-
cally active species.[11] These mechanochemical reactions are
conducted under aerobic reaction conditions and in the
absence of ligands or solvent. Furthermore, as the source of
the catalytic material is the reaction vial, which is recoverable
and reusable, the whole synthetic process is environmentally
benign, safe, convenient to set-up, inexpensive, and recycla-
ble. We envisioned that these reaction conditions would be
extremely versatile and suitable for the cyclopropanation of
alkenes with diazoacetates.
For our initial experiment, we milled methyl phenyl-
diazoacetate (1) and styrene as a neat reaction mixture in
a copper vial with a copper ball bearing, which afford the
corresponding cyclopropane product 2 in 70% yield and a low
diastereomeric ratio (65:35) favoring the E isomer (Table 1,
entry 1). For comparison, when a nickel vial and ball system
was used, 2 was formed in a lower yield and with comparably
low diastereoselectivity (< 31% yield, 60:40 d.r.; entry 2).
Two catalytically inactive metals/materials were also tested
and yielded no product or dimer side products, which suggests
that the cyclopropanation reaction is not a purely mechanical
phenomenon (entries 3 and 4). Encouraged by the activity
and selectivity achieved in the homogenous AgSbF6 catalyzed
cyclopropanation of sterically demanding alkenes in dichloro-
[*] L. Chen, M. O. Bovee, J. Mack
Department of Chemistry, University of Cincinnati
Cincinnati, OH 45220 (USA)
E-mail: james.mack@uc.edu
B. E. Lemma, K. S. M. Keithley, S. L. Pilson, M. G. Coleman
Department of Chemistry, Rochester Institute of Technology
Rochester, NY 14623 (USA)
E-mail: mgcsch@rit.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504236.
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Table 1: Mechanochemical cyclopropanation of styrene with methyl
phenyldiazoacetate.
times, with an ethyl acetate solvent wash between consecutive
runs to remove the crude reaction mixtures, and observed
highly reproducible yields and no appreciable decrease in the
diastereoselectivity (97:3 d.r.; Figure 1).
Entry
Catalyst
Vial and ball
Yield[a] [%]
E/Z[b]
1
2
3
4
5
6
7
8
9
–
–
–
–
copper
nickel
stainless steel
Teflon
stainless steel
copper
nickel
Teflon
copper
stainless steel
stainless steel
Teflon
nickel
stainless steel
copper
nickel
stainless steel
copper
70
31
NR
NR
92
90
92
65
75
88
96
40
72
62
75
52
45
38
35
65:35
60:40
–
–
Ag shot
Ag shot
Ag shot
Ag shot
Ag foil
Ag foil
Ag foil
Ag foil
Ag foil
CuI
CuI
CuI
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
97:3
90:10
95:5
97:3
95:5
98:2
98:2
97:3
97:3
55:45
55:45
55:45
90:10
90:10
90:10
10[c]
11
12
13
14[d]
15[d]
16[d]
17[d]
18[d]
19[d]
nickel
All reactions were conducted with a 1:5 ratio of the diazoacetate and the
olefin at 17.4 Hz. [a] Yield of isolated product (<5% of the diazoacetate
dimer was observed). [b] Determined by 1H NMR spectroscopy.
[c] 20.3 Hz. [d] Catalyst loading: 2.5 mol%.
Figure 1. Recyclability of the silver foil as a cyclopropanation catalyst.
Using the same silver-metal foil, we extended the scope of
the cyclopropanation by exploring the electronic and steric
effects of substituted styrene derivatives and various other
olefins in the presence of diazoacetate 1 (Table 2). Both
methane, we set out to test the efficacy of a heterogeneous
silver metal catalyst.[12] Gratifyingly, milling 1 and styrene in
a stainless-steel vial charged with a silver shot generated the
cyclopropanation product in nearly quantitative yield (92%
yield) and high diastereomeric ratio (97:3) when the reaction
mixture was mechanically mixed with a stainless-steel ball
bearing (entry 5). This is in good agreement with the yield and
stereoselectivity achieved in the homogenous silver(I)-cata-
lyzed counterpart.[12] Interestingly, bimetallic heterogeneous
mixtures yielded inferior results irrespective of the source of
the silver catalyst that was added to the metallic reactor and
ball system (entries 6, 7, 9, and 13). Moreover, Teflon vials
and balls also resulted in inferior yields but maintained the
high diastereoselectivity (97:3) in the presence of silver,
suggesting that the decreased ball mass likely resulted in
a significantly lower mechanical force that occurred during
the molecular collision events (entries 8 and 12). The addition
of a catalytic amount of copper(I) iodide to the metal vial and
ball system was found to be detrimental to both the yield and
the diastereoselectivity (entries 14–16). On the other hand,
the addition of palladium(II) acetate, a metal that is rarely
used for cyclopropanation reactions with diazoacetates,
resulted in good diastereoselectivity (90:10), but only
modest yields of the cyclopropanation product (entries 17–
19).[13]
Table 2: Effect of the alkene structure on the reactivity.
Entry R1
R2
R3
R4
Product Yield[a] [%] E/Z[b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4-MeOC6H4
H
H
H
H
H
H
CH3
H
H
H
H
C6H5
H
H
H
H
H
H
H
H
H
CH3
H
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
H
H
3
4
5
6
7
90
92
89
90
85
96
88
86
82
35
58
89
85
89
NR
NR
92:8
96:4
98:2
95:5
98:2
98:2
85:15
92:8
85:15
NA
NA
NA
95:5
98:2
–
4-MeC6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
4-tBuC6H4
C6H5
C6H5
C4H9
C6H5
C6H5
8
9
10
11
12
13
14
15
16
C6H5
1-naphthyl
2-naphthyl
C6H5
H
C6H5 C6H5 C6H5
C6H5 C6H5
C6H5
H
–
Having identified optimized conditions for the heteroge-
neous silver(0)-catalyzed cyclopropanation reaction, we set
out to test the recyclability of this mechanochemical process.
We conducted the cyclopropanation reaction five consecutive
All reactions were conducted with a 1:5 ratio of the diazoacetate and the
olefin. [a] Yield of isolated product (<5% of the diazoacetate dimer was
1
observed). [b] Determined by H NMR spectroscopy.
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electron-rich and electron-poor styrene derivatives afforded
the corresponding cyclopropane products 3–8 in high yields
and diastereoselectivities (entries 1–6). A modest diastereo-
meric ratio (85:15) was observed for a-methylstyrene
(entry 7), whereas b-methylstyrene afforded the correspond-
ing cyclopropane 10 in both good yield and diastereoselec-
tivity (entry 8). Under our optimized ball-milling conditions,
1-hexene was converted into cyclopropane 11 with a slightly
lower diastereomeric ratio (85:15) than in previous reports
(entry 9).[14] Both trans- and cis-stilbene smoothly underwent
the mechanochemical reaction to give the corresponding
products 12 and 13 in high diastereomeric ratios, but low
yields (entries 10 and 11). 1,1-Diphenylethylene and vinyl-
naphthalene compounds are also highly effective substrates
for the diastereoselective cyclopropanation reaction under
ball milling (entries 12–14). Finally, 1,1,2,2-tetraphenyl-
ethylene and 1,1,2-triphenylethylene were found to be
unreactive under these mechanochemical reaction conditions,
likely because of steric hindrance (entries 15 and 16).
propanation of alkenes with diazoacetates under solvent-free
mechanochemical reaction conditions. The chemically inert
stainless-steel vial and ball reactor transfers sufficient kinetic
energy and mixes the reaction mixture to enable product
formation without producing any detectable amounts of the
cyclopropane ring-opening side products. Future work will
apply these mechanochemical reaction conditions to other
metal-catalyzed reactions for the development of catalytically
active and selective heterogeneous catalysts for carbene
transfer reactions.
Acknowledgements
This research is supported by the National Science Founda-
tion (CHE-1058627 and CHE-1156449) and the University of
Cincinnati Research Council (URC). We would also like to
thank the Rochester Institute of Technology, College of
Science for financial support through a FEAD grant.
The electronic character of substituted diazoacetate
compounds can be generally categorized by their resultant
characteristic reactivities. As such, three distinctly different
classes, namely acceptor-only, acceptor–acceptor, and donor–
acceptor diazoacetate families, were tested for the silver(0)-
catalyzed cyclopropanation of styrene under mechanochem-
ical milling conditions (Table 3). Both electron-rich and
electron-poor donor–acceptor diazoacetates were efficiently
Keywords: cycloaddition · green chemistry ·
heterogeneous catalysis · solid-phase synthesis ·
sustainable chemistry
How to cite: Angew. Chem. Int. Ed. 2015, 54, 11084–11087
Angew. Chem. 2015, 127, 11236–11239
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Received: May 8, 2015
Published online: July 29, 2015
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