The effect of catalyst loading in copper-catalyzed cyclohexane functionalization by carbene insertion

Article abstract of DOI:10.1002/ejic.200600811

A study of the variables that affect the insertion of the :CHCO ₂Et group (formed from ethyl diazocetate, EDA) into the C-H bonds of cyclohexane in the presence of a Tp^xCu complex as the catalyst (Tp^x = trispyrazolylborate ligand) has demonstrated an anomalous effect of the catalyst loading. The use of low concentrations of catalyst produces an increase in the yield of the C-H activation product ethyl cyclohexaneacetate. This effect has also been found in the case of other less elaborated catalysts such as [Bp^Br3Cu] or [(bipy)₂-Cu][I]. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejic.200600811

FULL PAPER
DOI: 10.1002/ejic.200600811
The Effect of Catalyst Loading in Copper-Catalyzed Cyclohexane
Functionalization by Carbene Insertion
Ana Caballero,[a] M. Mar Díaz-Requejo,[a] Swiatoslaw Trofimenko,[b]
Tomás R. Belderraín,*[a] and Pedro J. Pérez*[a]
Keywords: Copper / C–H activation / Homogeneous catalysis / Carbenes / N ligands
A study of the variables that affect the insertion of the
:CHCO2Et group (formed from ethyl diazocetate, EDA) into
the C–H bonds of cyclohexane in the presence of a TpxCu
complex as the catalyst (Tpx = trispyrazolylborate ligand) has
demonstrated an anomalous effect of the catalyst loading.
The use of low concentrations of catalyst produces an in-
crease in the yield of the C–H activation product ethyl cyclo-
hexaneacetate. This effect has also been found in the case of
other less elaborated catalysts such as [BpBr3Cu] or [(bipy)2-
Cu][I].
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
Diazo reagents have been employed extensively as a car-
bene source, initially under thermal or photochemical con-
ditions and in the last decades with the aid of transition-
metal complexes as catalysts for several transformations[1]
for the transfer of the carbene unit to many saturated and
unsaturated substrates (Scheme 1). Besides the desired ad-
dition or insertion products, the undesired carbene coupling
side-reaction has usually been observed in the vast majority
of reported systems.
It is well established that the transformations depicted in
Scheme 1 take place through the intermediacy of a metallo-
carbene species LnM=CR1R2, which is generated from the
direct reaction of the catalyst MLn and the diazo com-
pound,[1] and that this constitutes the rate-determining step
of the overall process.[2,3] The transient metallocarbenoid
Scheme 1. Transition-metal-catalyzed carbene transfer from diazo
compounds.
species (MC) usually displays an electrophilic behavior,[4] tion of the copper carbene complex [(N–N)Cu=CPh2] from
which explains its reactivity towards the nucleophiles avail- the reaction of a diketiminatocopper(I) complex and
able in solution Ϫ the diazo compound or the target sub- Ph2CN2.[6]
strate to be functionalized. Due to its high reactivity, there
In recent years we have described the potential of a fam-
are few reports in the literature in which these intermediates ily of complexes of general formula [TpxCu(NCMe)] (Tpx
have been detected or isolated. In the case of copper, the = homoscorpionate ligand) toward the two processes men-
first observation of one of these species under catalytic con- tioned above: the addition of :CHCO2Et from ethyl diazo-
ditions is due to Straub and Hofmann.[5] Later, Warren and acetate (EDA) to multiple carbon–carbon bonds (alkenes,[7]
Dai described the preparation and structural characteriza- alkynes,[8] aromatics[9]) or its insertion into single X–H
bonds (alkanes,[10] amines,[11] alcohols[12]). All these trans-
formations are accompanied by the copper-catalyzed car-
bene coupling reaction, which leads to the formation of di-
[a] Laboratorio de Catálisis Homogénea, Departamento de Quím-
ethyl fumarate and maleate in variable yields [Equation (1)].
ica y Ciencia de los Materiales, Universidad de Huelva-Unidad
In this contribution, we present the results obtained during
the course of our investigations focused on the study of the
variables that could affect the formation of these undesired
by-products with the aim of its decrease or suppression. We
Asociada al CSIC,
Campus de El Carmen, 21007 Huelva, Spain
[b] Department of Chemistry and Biochemistry, University of Del-
aware,
Newark, DE 19716, USA
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Anomalous Effect of Catalyst Loading
FULL PAPER
have found an unexpected effect of the catalyst loading that studied the effect of the following variables that could affect
affects the chemoselectivity of these transformations not the chemoselectivity induced by a given catalyst: (a) the ad-
only in the case of the [TpxCu(NCMe)] catalysts but also dition rate of EDA, (b) the concentration of EDA, and (c)
with other less elaborated catalysts. This knowledge has al- the catalyst loading.
lowed the enhancement of the yields of the desired prod-
ucts.
Effect of EDA Concentration and Addition Time
The traditional experimental methodology in metal-cata-
lyzed diazo compound decomposition usually employs a
large excess of substrate with respect to the diazo com-
pound, as well as slow addition devices to add the latter to
Results and Discussion
the solution containing the catalyst and the substrate.[1,13]
With this experimental design, the [diazo compound]/[cata-
lyst] ratio in the reaction mixture can be maintained at low
values, thereby minimizing the formation of DEF and
DEM. To verify this common behavior, we have run a series
of five experiments for the reaction of cyclohexane and
EDA in the presence of 1 or 2 in which only the time em-
ployed for the addition of EDA was varied. Figure 1 (left)
shows the conversion into ethyl cyclohexaneacetate ob-
tained at the end of each experiment (determined from the
NMR spectra of the crude reaction mixture). Those carried
out at t = 0 h were performed by adding the diazo com-
pound in one portion, whereas the others were run with the
aid of a syringe pump programmed to add the EDA
(1 mmol dissolved in 10 mL of cyclohexane) over 1, 3, 6
and 12 h. An increase in the yields of the desired product
was observed upon lengthening the addition time, although
for the TpMs-containing catalyst this increase was not as
high as with the TpBr3 catalyst. The use of the latter in a
series of experiments in which only the concentration of
EDA in the feed solution was varied gave the results shown
on the right-hand side in Figure 1: the lower the value of
[EDA], the higher the yield of the desired product. Overall,
both sets of experiments are in agreement with the men-
tioned effect of the [EDA]:[catalyst] ratio in the reaction
mixture: a low value of this ratio enhances the yield of the
desired product and decreases the yields of DEF and DEM.
We have previously reported[10] that the complexes
[TpBr3Cu(NCMe)] (1) and [TpMsCu] (2) catalyze the inser-
tion of EDA into the C–H bonds of cyclohexane
(Scheme 2), leading to the formation of ethyl cyclohex-
aneacetate as well as diethyl fumarate (DEF) and maleate
(DEM). Under the same conditions (1:20:2000 for [catalyst-
]:[EDA]:[C6H12], 0.05 mmol of catalyst) 1 and 2 gave 90 and
54% yield of ethyl cyclohexaneacetate, respectively, with
DEF and DEM accounting for the remaining EDA. In or-
der to diminish such amounts of non-desired products, we
Scheme 2. [TpxCu]-catalyzed cyclohexane functionalization by
EDA insertion.
Figure 1. Variation of the yield of ethyl cyclohexaneacetate with EDA addition time (left) and the EDA concentration added from the
syringe pump {[TpBr3Cu(NCMe)] as the catalyst}.
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T. R. Belderraín, P. J. Pérez et al.
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Effect of the Catalyst Loading
which is based on the use of slow addition devices for EDA,
prevents us from carrying out reliable kinetic studies. How-
ever, the importance of the discovery of the effect of the
catalyst loading in this transformation, which gives a no-
ticeable enhancement in the yields simply by decreasing the
amount of catalyst, should be pointed out. At this point,
we wondered about the extension of this proposal to other
copper-based catalysts. The number of catalytic systems
based on copper for the intermolecular insertion of diazo
compounds into C–H bonds is very limited,[15] the highest
conversions thus far being obtained with our TpxCu sys-
tem.[10] In contrast, there are more examples for the intra-
molecular version, including chiral catalysts that have led
to moderate to high degrees of enantioselectivity.[16] The li-
gands bound to the copper center in these cases were prefer-
entially bis-oxazolines and bis-imines, i.e., ligands with two
nitrogen donor atoms. However, there are no reports of the
use of these catalysts for the intermolecular, asymmetric in-
sertion of diazo compounds into C–H bonds. In the search
for model complexes for the above chiral systems, we de-
cided to study the catalytic properties of the complex
[BpBr3Cu] (4), which is similar to the [BpxCu] complexes
already reported by other authors.[17] Table 1 shows the re-
sults obtained for the reaction of EDA and cyclohexane in
the presence of 4. In one-portion addition reactions, only
an 8% yield of ethyl cyclohexaneacetate was observed with
a 0.05 mmol catalyst loading. This yield was improved up
to 13% when performing the slow addition of EDA over
3 h (entry 2). Although modest, it is worth pointing out that
these data compare well with those shown in Figure 1 for 2
as the catalyst under the same conditions. Following the
strategy learnt from the previous sections, we used a lower
catalyst loading (0.002 mmol) of 4 and observed the desired
effect: the yields were enhanced up to 36 and 49% with
EDA addition times of 4 and 17 h, respectively. We find
these results quite remarkable in two ways: first, they dem-
onstrate the catalytic capability of a copper complex with a
bidentate, not tridentate, Bpx ligand, with yields similar to
those obtained with 2, and secondly, they demonstrate that
the steric protection assumed for the TpxCu system seems
not to be as crucial as initially supposed, and that other
factors, such as the electron-withdrawing nature of the li-
gand and catalyst loading, could be very important at this
point.
Another approach to ensure the above conditions, i.e., a
low [EDA]:[catalyst] ratio is to employ a higher catalyst
loading at a fixed EDA concentration and addition time
(6 h). Surprisingly, when we employed a fivefold amount
of the catalyst (0.25 mmol instead of the 0.05 mmol in the
previous experiments), we did not observe any increase in
the yields of ethyl cyclohexaneacetate but the opposite effect.
As shown in Figure 2, a certain decrease occurred with 1
(from 88 to 70%) as the catalyst, whereas no response to
this variable was obtained from the experiment with 2 and
the same catalyst loading (ca. 16% in both cases). We then
explored the use of different catalyst loadings in the range
0.002 to 0.25 mmol, with the results displayed in Figure 2.
An unexpected increase in the degree of conversion of cy-
clohexane and EDA into ethyl cyclohexaneacetate took
place when the catalyst concentration was decreased in both
cases. No EDA was detected by GC shortly after the ad-
dition was completed, which is an indication of the ease
with which catalysts 1 and 2 consume the diazo compound.
The main yield enhancement in the case of the TpMsCu
catalyst appeared on going from 0.01 to 0.002 mmol as the
catalyst loading, which corresponds to an increase of nearly
45% (from 25 to 70%). This is a completely unexpected
behavior since such an increase takes place in the direction
in which the [EDA]:[catalyst] also increases, which is exactly
the contrary to that found above when EDA addition time
or EDA concentration were studied. It is also worth men-
tioning that this anomalous effect is not observed with sty-
rene as the substrate. In this case, a similar study was car-
ried out but no effect of the catalyst loading was observed.
This is in good agreement with the fact that styrene is much
more reactive than a cyclohexane C–H bond, and there is
no real competition between cyclopropanation and the
EDA decomposition toward diethyl fumarate and maleate.
Complex 4 could be a good model for anionic chiral li-
gands (semicorrines, some bisoxazolines), but many others,
including those referred to above, are neutral in nature. In
order to check the validity of our proposal, we ran a few
experiments using [(bipy)2Cu][I] (5) as the catalyst for the
insertion of EDA into the C–H bonds of cyclohexane. We
anticipated a very low catalytic activity for this complex in
this reaction since (a) no electron-withdrawing groups are
bonded to the metal center and (b) it appears to be coordi-
natively and electronically saturated. However, previous
studies with this complex for the cyclopropanation of sty-
rene have shown that bipy de-coordination takes place easi-
Figure 2. Effect of the catalyst loading on the yields in ethyl cyclo-
hexaneacetate.
Scope of this Methodology
We have not been able to find a reasonable explanation ly.[3a] Under our standard conditions (0.05 mmol of 5,
for this behavior[14] as our experimental methodology, 1 mmol of EDA, one portion addition of the diazo ester),
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Anomalous Effect of Catalyst Loading
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a Varian Saturn 2100T. GC analysis was performed with a Varian
CP-3800. Solvents were dried and degassed before use. All reagents
were purchased from Aldrich and employed without any further
purification. The synthesis of the copper catalysts[7–10] was carried
out as reported previously.
General Catalytic Experiment: [TpxCu] (0.05 mmol) was dissolved
in a mixture of CH2Cl2 (10 mL) and cyclohexane (10 mL). A solu-
tion of EDA (1 mmol) in cyclohexane (10 mL) was slowly added
during the programmed time with the aid of a syringe pump, at
room temperature. No EDA was detected at the end of the reaction
by GC, only ethyl cyclohexaneacetate and diethyl fumarate and
maleate. Other experiments were performed by adding the pure di-
azo compound in one portion. For those experiments carried out
without cyclohexane, dichloromethane were employed as the sole
solvent.
Table 1. Use of [BpBr3Cu] (4) and [(bipy)2Cu][I] (5) as catalysts for
the reaction of ethyl diazoacetate and cyclohexane.[a]
The reported yields correspond to an average of at least of two
runs, and were determined in the following manner. After removal
Catalyst loading EDA addition time [BpBr3Cu][b] [(bipy)2Cu][I][b]
1
[mmol]
[h]
of volatiles, the crude product was investigated by H NMR spec-
troscopy, with a standard compound being added (tosyl chloride
or styrene) to ensure that all the initial EDA was converted in the
observed products. The observed ratios were compared to those
from GC analysis in order to establish the response factors, which
were later employed in the subsequent experiments to determine
the yields. The products were identified by comparison with com-
mercial samples (ethyl cyclohexaneacetate, diethyl fumarate and
maleate) or with data already reported.
0.05
0.05
0.002
0.002
0.002
one portion
8
nd
–
10
18
–
3
4
12
17
13
36
–
49
[a] See Experimental Section. [b] Yields calculated by NMR spec-
troscopy, with DEF and DEM formation accounting for 100% of
EDA.
no ethyl cyclohexaneacetate was observed, with only DEF
and DEM being detected at the end of the reaction. This
could be enough to discard 5 (or any other complex) as a
potential catalyst. However, based on our proposal, we ran
two experiments with a lower catalyst loading and, with the
aid of a syringe pump, with a total addition time of 4 and
12 h, the yields of the desired product increased up to 10
and 18%, respectively. Again, these results indicate that,
even for very low activity and non-elaborated catalysts, the
catalyst loading affects the chemoselectivity of the reaction.
Acknowledgments
We thank the Ministerio de Educación y Ciencia for funding (Pro-
yecto CTQ2005-00324BQU) and reserach fellowship (A. C.). The
Ramón y Cajal Programme is also thanked (M. M. D. R.).
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Conclusions
We have discovered that the formation of diethyl fumar-
ate and maleate in the presence of [TpxCu] is influenced by
the catalyst loading in the opposite sense that would nor-
mally be expected. The use of very low concentrations of
the [TpxCu] catalysts causes a decrease in the formation of
DEF and DEM and a concomitant increase in the yields of
the desired C–H-functionalized product. These findings
have been extended to copper complexes with bidentate li-
gands as models for other already known catalysts. We be-
lieve that these results could be extended to many already
known systems for the copper-catalyzed carbene transfer
from diazo compounds, thereby opening up a new perspec-
tive in the copper-catalyzed insertion of diazo compounds
into C–H bonds.
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Experimental Section
1
General: H NMR spectra were run at 400 MHz and 13C NMR at
100 MHz, with CDCl3 as solvent. Mass spectra were recorded with
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T. R. Belderraín, P. J. Pérez et al.
FULL PAPER
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[13] In some cases the diazo compound has been added in one por-
tion at the beginning of the reaction. See, for example, ref.[7]
[14] The experimental data available have not been fitted into a
mechanistic proposal that accounts for all them. A referee has
noted that radical species could perhaps be involved in this
transformation. A previous study concerning the use of
[Tp*Cu] as the catalyst for carbene and nitrene transfer has
shown that radicals could be responsible for the transfer only
in the latter case. See: M. M. Díaz-Requejo, P. J. Pérez, M.
Brookhart, J. L. Templeton, Organometallics 1997, 16, 4399–
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Received: September 1, 2006
Published Online: December 5, 2006
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