Complete control of the chemoselectivity in catalytic carbene transfer reactions from ethyl diazoacetate: An N-heterocyclic carbene-Cu system that suppresses diazo coupling

Article abstract of DOI:10.1021/ja047284y

The complex IPrCuCl (1) catalyzes the transfer of the :CHCO₂Et group from ethyl diazoacetate (EDA) to unsaturated and saturated substrates (olefins, amine, alcohols) with very high yields. In the absence of substrate, the complex 1 does not react with EDA to give the diazo coupling products (fumarate and maleate), a rare example in the field of metal-catalyzed diazocompounds decomposition. Copyright

Full text of DOI:10.1021/ja047284y

Published on Web 08/14/2004
Complete Control of the Chemoselectivity in Catalytic Carbene Transfer
Reactions from Ethyl Diazoacetate: An N-Heterocyclic Carbene-Cu System
That Suppresses Diazo Coupling
Manuel R. Fructos,† Toma´s R. Belderrain,† M. Carmen Nicasio,† Steven P. Nolan,‡ Harneet Kaur,‡
M. Mar D´ıaz-Requejo,*,† and Pedro J. Pe´rez*,†
Departamento de Qu´ımica y Ciencia de los Materiales, UniVersidad de HuelVa, Campus de El Carmen
21007-HuelVa, Spain, and Department of Chemistry, UniVersity of New Orleans, New Orleans, Louisiana 70148
Received May 10, 2004; E-mail: perez@dqcm.uhu.es; mmdiaz@dqcm.uhu.es
Scheme 1. Transition-Metal-Catalyzed Carbene Transfer from
Diazocompounds
Diazocompounds have been extensively employed as a carbene
source in organic synthesis.1 In the past decade, the incorporation
of such fragments to a variety of substrates has been accomplished
in many cases with the aid of an appropriate transition-metal
complex acting as catalyst.2 It is well-established that this trans-
formation occurs via an electrophilic metallocarbene intermediate,2,3
although this species has only been detected once.4 As shown in
Scheme 1, the transfer of the carbene unit to a nucleophile affords
the desired product and releases the metal center to reinitiate the
catalytic cycle. The main drawback of this methodology is the
existence of an undesirable side reaction, the homocoupling of the
diazocompound (Scheme 1, left). This problem has been usually
overcome by using slow addition devices and/or using excess of
the nucleophilic substrate. The vast majority of systems capable of
mediating this reaction bear nitrogen-donor ligands,1 and they all
display a similar behavior: ethyl diazoacetate is readily converted
into diethyl fumarate and maleate because of this unwanted side
reaction. On the other hand, phosphorus-containing ligands are not
useful for this chemistry because of the facile carbene transfer to
phosphorus to produce ylide derivatives.
Scheme 2. Reactions of EDA in the Presence of 1
During the course of our investigations aimed at developing new
catalysts that could avoid the aforementioned diazo coupling
reaction, we examined the potential of complexes containing the
emerging N-heterocyclic carbene (NHC) ligands5 toward the
diazocompound decomposition reaction in the presence of several
substrates. NHC-based catalytic systems have been reported for
several processes such as hydrogenation,6 hydrosilylation,7 C-C8
and C-N9 bonds formation, olefin metathesis,10 and ATRP.11
However, very few examples (Ru- and Rh-based) of application to
diazo decomposition and carbene transfer have been reported using
such systems.12
We prepared complex IPrCuCl13 (1) [IPr: 1,3-bis(diisopropyl-
phenyl)imidazole-2-ylidene] and employed it as catalyst in two test
experiments (Scheme 2): the cyclopropanation of styrene with ethyl
diazoacetate (EDA) and the decomposition of EDA to give fumarate
and maleate. In both cases, a solution of 0.025 mmol of 1 in
dichloromethane was mixed with 0.625 mmol of EDA, for a 1:25
EDA/catalyst ratio (4% of catalyst). In the cyclopropanation test,
3.25 mmol of styrene was also added (1:25:125 molar ratio for
[1]/[EDA]/[styrene]).
batches of catalyst and EDA, leading to identical results: in the
absence of styrene, EDA did not decompose to any extent in the
presence of 1.
Two kinetic experiments were conducted to monitor the lifetime
of EDA in the presence of 1. Solutions of 1 and EDA were prepared,
stirred at room temperature, and periodically monitored by GC to
quantify the amount of EDA present in the reaction mixture. No
decomposition of EDA was observed after 3 h. After this time,
styrene (4 equiv with respect to EDA) was added to one of the
solutions, inducing the immediate consumption of EDA, as inferred
from the observed decay and the subsequent formation of cyclo-
propane products in very high yield (Figure 1). The non-styrene-
containing solution did not undergo any noticeable change along
the time interval studied (13 h), in what can be considered a rare
example in the field of metal-catalyzed diazocompound decomposi-
tion.2,14 Styrene and cyclooctene could be readily converted into
the corresponding cyclopropanes in nearly quantitative yields in
the presence of 1 (Table 1), affording the diastereoselectivities cis/
trans 32:68 and exo/endo 73:27, respectively. We have also studied
the related insertion of the :CHCO2Et unit into the X-H bonds of
amines and alcohols. The N-H bonds of aniline or pyrrolidine, as
well as the O-H bonds of ethanol or sec-butanol, were function-
alized, following a similar procedure to that used with styrene. Very
high product yields (Table 1, entries 3-6) have been obtained, the
amounts being comparable to those of very active copper-based
catalysts already known.15 Previously reported copper(I) complexes
displayed an extremely high activity2 toward EDA decomposition,
in contrast with the observed behavior of IPrCuCl, which does not
react with EDA. Substrate (olefin, amine, and alcohol) addition
After stirring the solution for 6 h, we monitored the reaction
mixtures by GC. The styrene-containing solution showed a greater
than 90% conversion to cyclopropanes (referenced to EDA), with
no remaining diazoester being detected. Surprisingly, the experiment
carried out with EDA alone showed no consumption of the diazo
reagent, the catalyst remaining unaffected for prolonged time
periods. These experiments were repeated four times, using different
† Universidad de Huelva.
‡ University of New Orleans.
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10.1021/ja047284y CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
containing 1 and EDA initiated consumption of the diazoester.
Similar behavior was observed with all substrates shown in Table
1, as well as with other weak donors such as benzene. A possible
explanation might involve the formation of an active species being
a substrate-containing complex, probably cationic in nature, with
chloride as a counterion.
In conclusion, we have shown that complex IPrCuCl catalyzes
the transfer of the :CHCO2Et group (from ethyl diazoacetate) to
unsaturated and saturated substrates (olefins, amine, alcohols) with
very high yields. The unique behavior of this system constitutes,
in our opinion, the starting point for the development of new
catalysts that avoid the already mentioned main drawback of this
methodology, the diazocompound dimerization reaction.
Acknowledgment. This communication is dedicated to the
memory of Dr. Juan Carlos del Amo Aguado. We thank the MCYT
(Proyecto BQU2002-01114) for financial support and the Univer-
sidad de Huelva for the Servicio de Resonancia Magne´tica Nuclear.
M.R.F. thanks the MCYT for a research studentship. M.M.D.R.
thanks the MCYT for a Ramo´n y Cajal grant. S.P.N. acknowledges
the National Science Foundation for support of the work performed
at UNO.
Figure 1. EDA decomposition in the presence of 1. (1) EDA as the sole
reagent. (2) Styrene added at 3 h. Dibromomethane used as internal
standard.
Table 1. Carbene Transfer from Ethyl Diazoacetate (EDA) Using
1 as the Catalysta
Supporting Information Available: General experimental proce-
dures and NMR spectra of the products in Table 1 (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
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a Reactions performed at room temperature with 0.025 mmol of 1, 4%
with respect to EDA. b Percentage of the product, based in EDA, determined
by GC after total consumption of EDA with dibromomethane as internal
standard. Diethyl fumarate and maleate accounted for the remaining EDA.
Isolated yields are given in brackets. Average of two runs. c EDA added in
3 portions. d Addition of EDA in 1 portion gave a 10% of the disubstituted
PhN(CH2CO2Et)2. Addition in 2 portions avoided the double activation.e 1
portion addition. f X ) 10. g X ) 6.
leads to initiation of the catalytic cycle and to a species that has
preferred interaction with the diazo reagent yet in the absence of
substrate is inactive toward diazo activation (and degradation).
Therefore, the chemoselectivity in this system appears to be self-
controlled and requires the presence of a substrate in the reaction
mixture, a result that, to our knowledge, finds no precedent in the
metal-mediated catalytic carbene transfer from ethyl diazoacetate.
It is also worth mentioning that reactions were performed with
simultaneous addition of EDA and substrate, without the need for
slow addition techniques, at room temperature, with excess of the
substrate. We have also performed the equimolar EDA/substrate
experiments, with the results shown in Table 1. The olefins were
converted into cyclopropanes with a ca. 70% yield, whereas higher
conversions were observed for amines and alcohols.16 The prefer-
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competition experiment carried out with styrene and aniline yielding
the aniline derivative as the major product (<95%).
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Although mechanistic studies are currently underway, we believe
that the absence of the reactivity of 1 toward EDA suggests that 1
is not the active catalytic species and that the substrate helps
generate the active species responsible for diazo decomposition.
In fact, the addition of a small amount (nearly stoichiometric
referred to catalyst) of diethyl fumarate or maleate to a solution
(16) A reviewer noted that a copper-based catalyst provided very good yields
for the cyclopropanation reaction using a 1:1.2 ratio of styrene and the
diazoester (BHT derivative). That same catalyst with ethyl diazoacetate
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