Carbenoid transfer in competing reactions catalyzed by ruthenium complexes

Article abstract of DOI:10.1002/aoc.3094

Aiming at improving catalyst activity, ten ruthenium promoters have been investigated in carbenoid transfer from ethyl diazoacetate to styrene as a model substrate. Optimal selectivity in cyclopropanation has been attained with the new NHC-Ru complex 10, as well as with the Fischer carbene 7. The surprising non-metathetical behavior of the Grubbs' first-generation catalyst in this multifaceted process is highlighted. Copyright

Full text of DOI:10.1002/aoc.3094

Full Paper
Received: 15 October 2013
Accepted: 20 October 2013
Published online in Wiley Online Library: 29 January 2014
(wileyonlinelibrary.com) DOI 10.1002/aoc.3094
Carbenoid transfer in competing reactions
catalyzed by ruthenium complexes
a
a
b,c
Ileana Dragutan *, Valerian Dragutan and Francis Verpoort *
Aiming at improving catalyst activity, ten ruthenium promoters have been investigated in carbenoid transfer from ethyl
diazoacetate to styrene as a model substrate. Optimal selectivity in cyclopropanation has been attained with the new NHC–
Ru complex 10, as well as with the Fischer carbene 7. The surprising non-metathetical behavior of the Grubbs’
first-generation catalyst in this multifaceted process is highlighted. Copyright © 2014 John Wiley & Sons, Ltd.
Keywords: ruthenium; carbene; cyclopropanation; metathesis; dimerization
(
Scheme 1) and as proceeding under the promotion of ten ruthe-
Introduction
nium pre-catalysts, including the new complexes 4 and 10
(Scheme 2). As a certain control on undesired processes accompa-
nying cyclopropanation can be exerted by modulating reaction
A diversity of therapeutic agents and natural or unnatural com-
pounds endowed with biological activity include cyclopropane
[
1]
as a basic structural unit. The ability of cyclo-
propane to induce substantial conformation
constraints promotes incorporation of this
highly strained and reactive carbocycle in
complex structures in need of a particular
stereoconfiguration. In this context, a high-
yielding and stereocontrolled construction of
[
2]
the cyclopropane motif by metal-free or
metal-catalyzed intermolecular cyclopro-
[3]
panation has for years been a challenging
[
4]
task for organic chemists.
A leading
pathway to access cyclopropane-containing
derivatives is carbenoid cyclopropanation cata-
lyzed by transition metal promoters, among
which ruthenium complexes recently enjoy a
[5]
renewed recognition. It should be kept in
mind, however, that in ruthenium-induced
cyclopropanation several concurrent C–C cou-
pling transformations, such as metathesis and
homocoupling, frequently intervene. Advocat-
ing present trends for environmentally benign
and cost-effective processes, use of more
selective catalysts for cyclopropanation may
have far-reaching consequences, in particular
for the drug industry.
Scheme 1. Monitoring the reaction of styrene with ethyl diazoacetate induced by ruthenium cata-
lysts (IR spectra for decomposition of N CHCOOEt versus time; GC and NMR for product identification).
2
Results and Discussion
*
Correspondence to: Ileana Dragutan and Francis Verpoort, Institute of Organic
Chemistry of the Romanian Academy, 060023 Bucharest, Romania and Wuhan
University of Technology, 430070 Wuhan, China. Email: idragutan@yahoo.com;
francis.verpoort@ugent.be
Here we report for the first time on the performance of a creative
selection of structurally diverse ruthenium catalysts screened for
concurrent cyclopropanation and metathesis, under identical
reaction conditions. The high-yield valorization of the commer-
cial first-generation Grubbs catalyst in the stand-alone
cyclopropanation of styrene with diazoacetate is also showcased.
Progress of the reaction between styrene and ethyl diazoa-
cetate (EDA), generally accepted as the standard system for
cyclopropanation, was examined using complementary techniques
a Institute of Organic Chemistry of the Romanian Academy, 060023 Bucharest, Romania
b State Key Laboratory of Advanced Technology for Materials Synthesis and
Processing, Center for Chemical and Material Engineering, Department of Chemistry,
Faculty of Sciences, Wuhan University of Technology, Wuhan, 430070 China
c Department of Inorganic and Physical Chemistry, Ghent University, 9000 Ghent, Belgium
Appl. Organometal. Chem. 2014, 28, 211–215
Copyright © 2014 John Wiley & Sons, Ltd.

I. Dragutan et al.
Among the catalysts examined in
reactions performed under high dilu-
tion in toluene, at 60°C and with a
molar ratio of catalyst:EDA:styrene =
1:125:2500, the best chemoselectivity
for asymmetric intermolecular cyclo-
propanation was observed for the
novel IPr-containing promoter 10 and
the ethoxy Ru-carbene 7, yielding 1-
carbethoxy-2-phenylcyclopropane
with 85% and 84% selectivity,
respectively (Table 1). Moreover,
cyclopropanation is still the major re-
action pathway (72–77%) in the case
of catalysts 1, 3 and 4; the latter cata-
lyst, a new complex bearing an O,
N-bidentate Schiff base and two
PPh ligands, showed excellent activ-
3
ity in cyclopropanation (91.1% yield).
Importantly, data on application
of catalysts 5 and 6 as initiators
in the ubiquitous cyclopropanation
of styrene with diazo compounds
are, to our knowledge, quite scarce
and therefore we investigated in
more detail the behavior of these
catalysts in this process (see
[6–9]
Scheme 2. Ruthenium catalysts employed in reaction of styrene with EDA.
conditions, we decided to enhance cyclopropanation and
minimize EDA homocoupling (dimerization) by slowly adding a
diluted solution of the diazo compound to the mixture of excess
styrene and catalyst. Working under such low catalyst loadings,
metathesis is also expected to diminish, to the benefit of
cyclopropanation.
It should be remarked that Ru complexes 4, 7, 8 and 10 have not
been previously reported for cyclopropanation. Results obtained in
this study are compiled in Table 1. For all of the catalysts, selec-
tivity in cyclopropanation and metathesis is highlighted in Figs 1
and 2.
below). The first generation Grubbs catalyst 5 displays 35%
selectivity for cyclopropanation, with metathesis prevailing as
expected, while the second-generation Grubbs catalyst 6 gives
neither cyclopropanation nor dimerization (diazocoupling),
performing only metathesis (Table 1, entries 5 and 6). For
catalyst 6 everything seems to depend, however, on molar ratios
and reaction conditions, as disclosed in a related investigation
where, for a molar ratio of catalyst:EDA:styrene = 1:200:5200 in
chlorobenzene, at 60°C for 24 h, 1-carbethoxy-2-
phenylcyclopropane was predominantly formed and only <1%
metathesis was observed. [5]
If we consider now the competing side processes,
an exceptionally sharp increase in dimerization was
Table 1. Product distribution in the reaction of styrene with EDA (in toluene, at
evidenced for catalyst 9 (43%), quite close to the ex-
tent to which cyclopropanation occurs. Though also
a non-carbenic complex, the Schiff base bidentate-
Ru catalyst 4, as well as the ethoxy Ru-carbene 8,
largely favor metathesis over dimerization. The dis-
tinct behavior of 4 versus 1 (showing dimerization/
metathesis= 1) is likely due to a longer lifetime of
the metathesis-active species stabilized by the Schiff
base, relative to that arising from 1, in spite of the fact
that in both cases activation involves decoordination
a
6
0°C)
Reaction selectivity
Entry Catalyst Cyclopropanation (%) trans/cis Metathesis (%) Dimerization (%)
1
2
3
4
5
6
7
8
9
1
1
2
77
58
73
72
35
0
1.81
1.49
2.30
2.70
1.02
—
12
13
8
11
29
19
7
3
4
21
59
100
8
5
6
of the same phosphine (PPh3).
6
0
To our satisfaction, runs carried out with catalyst 5
7
84
50
44
85
0.98
1.38
1.21
1.47
8
at a still lower catalyst loading, in excess styrene, were
successes by all accounts, leading to higher selectivities
in cyclopropanation (Table 2). This is the more reward-
8
33
13
5
17
43
10
9
0
10
[10]
ing as, in an earlier report,
cyclopropanation was accomplished with as much as
0 mol% of catalyst 5, and at a more elevated
a tandem enyne
a
Based on EDA; determined by GC by comparison with authentic samples (internal
standard diethyl adipate). Ratio of dimerization products: diethylmaleate/
diethylfumarate ~2/1. cis- and trans-ethylcinnamate were found only in trace
amounts.
1
temperature (75°C). We were consequently encour-
aged to explore the influence of temperature on
cyclopropanation and the concurrent processes un-
der promotion by catalyst 5. In the range 30–50°C
b
Molar ratios: catalyst/EDA/styrene = 1/125/2500; toluene/styrene = 10.
Based on EDA; EDA was totally consumed.
c
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Appl. Organometal. Chem. 2014, 28, 211–215

Ru-catalyzed carbenoid transfer reactions
metathesis, while higher temperatures act in the opposite direction
Table 2). Our data demonstrate that dimerization is more sensitive
(
to temperature changes, diminishing from 23.5% to 8.5% while me-
tathesis abates only from 14.0% to 9.5%. It is noteworthy that vari-
ation of temperature in this range has no significant effect on the
trans:cis ratio of the cyclopropanated products, which oscillates
[
10]
around a value of 2, in agreement with literature reports.
Distribution between cyclopropanation, metathesis and dimer-
ization products observed in this work testifies to the complexity
of the chemical processes occurring simultaneously when adding
EDA to the mixture of styrene and catalyst, thus complying with
the generally accepted intervention of competitive mechanistic
pathways as illustrated in Scheme 3.
Figure 1. Varying selectivity in cyclopropanation products by change of
the Ru complex (1 to 10).
Experimental
General Information
1
H NMR spectra were recorded on a Bruker 300 MHz instrument
3
(in CDCl solution with tetramethylsilane as internal standard), in-
frared and Raman spectra were run on a Bruker FT-Raman/FT-IR
spectrometer, while capillary GC measurements were performed
using a Varian CDS 401. All materials were of analytical grade and
used without further purification. Catalysts 1, 2, 5 and 6 are com-
mercially available and were used without further purification.
[
7,19,20] [8] [8]
[9]
The ruthenium complexes 3,
synthesized according to literature procedures. The new catalysts
and 10 were obtained by treatment of complex 1 with the corre-
7,
8
and 9 (in situ) were
4
[
19–22]
Figure 2. Selectivity for the metathesis products, in the presence of Ru
complexes 1–10.
sponding Schiff base and NHC, respectively.
0 will be published elsewhere.
Details on 4 and
1
we found that selectivity in the desired cyclopropanation products
increased to 82.0%, while yields (based on EDA) increased from
Conclusions
7
2.7% to 90.6%, with dimerization and metathesis diminishing ac-
[11,12]
cordingly (Table 2).
An enhancement of cyclopropanation
In this communication the application profiles of ten ruthenium
pre-catalysts were explored to find an optimal choice for the
asymmetric cyclopropanation of styrene by carbene transfer from
EDA. It was found that the outcome depends considerably on the
nature and combination of ligands present in the coordination
sphere of ruthenium. Indeed, catalysts 1, 4, 7 and 10, bearing
at least two phosphines, exhibit great a propensity for
cyclopropanation. Our new NHC–Ru promoter 10 and the Fischer
carbene 7 were clearly shown to be superior in cyclopropanation,
even under low catalyst loading. Catalysts 2 and 9, which are
triggered into action by loss of a p-cymene unit, form a second
group with similar behavior, yet they appear as poorer promoters
of cyclopropanation; in comparison, the considerably higher
within the same temperature domain has been previously commu-
[
13]
nicated for the catalyst 1.
The first- and second-generation Grubbs catalysts (5 and 6), com-
[14]
monly applied in a variety of metathesis processes,
appear as
particular cases in cyclopropanation. Although these catalysts have
been employed in tandem metathesis/cyclopropanation reac-
[
10,15]
tions,
it is well documented that in the presence of diazo esters
[10,16]
catalyst 6 promotes mainly metathesis.
Of special interest here
also is that, in the presence of catalyst 5, the effect of reaction tem-
perature on cyclopropanation is totally different from that on the
dimerization and metathesis processes: lower temperatures re-
strain cyclopropanation to the advantage of dimerization and
Table 2. Influence of temperature on cyclopropanation, metathesis and dimerization in the
a
reaction of styrene with EDA, in the presence of Grubbs‘ catalyst 5
Reaction selectivity
Entry Temperature (°C) Cyclopropanation (%) trans/cis Metathesis (%) Dimerization (%)
1
2
3
4
5
30
35
40
45
50
62.5
71.0
73.0
77.0
82.0
2.2
1.9
1.8
1.9
2.0
14.0
11.0
9.0
23.5
18.0
18.0
14.5
8.5
8.5
9.5
a
In excess styrene. Molar ratios: catalyst/EDA/styrene = 1/400/8000.
Appl. Organometal. Chem. 2014, 28, 211–215
Copyright © 2014 John Wiley & Sons, Ltd.
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I. Dragutan et al.
Scheme 3. Competitive routes for metathesis and cyclopropanation in the reaction of styrene with EDA under Ru pre-catalyst promotion.
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