Very efficient, reusable copper catalyst for carbene transfer reactions under biphasic conditions using ionic liquids

Article abstract of DOI:10.1021/ol052564j

The complex {[HC(3,5-Me₂pz)₃]Cu(NCMe)}BF₄ catalyzes the transfer of the :CHCO₂Et unit from ethyl diazoacetate to several saturated and unsaturated substrates with very high yields and under biphaslc conditions using the ionic liquid [bmim][PF₆] and hexane as the reaction medium. The catalyst has been tested for several cycles of recovery and reuse without any loss of activity.

Full text of DOI:10.1021/ol052564j

ORGANIC
LETTERS
2006
Vol. 8, No. 4
557-560
Very Efficient, Reusable Copper Catalyst
for Carbene Transfer Reactions under
Biphasic Conditions Using Ionic Liquids
Pilar Rodr´ıguez, Ana Caballero, M. Mar D´ıaz-Requejo, M. Carmen Nicasio,* and
Pedro J. Pe´rez*
Laboratorio de Cata´lisis Homoge´nea, Departamento de Qu´ımica y Ciencia de los
Materiales, Unidad Asociada al CSIC, Campus de El Carmen s/n, UniVersidad de
HuelVa, 21007-HuelVa, Spain
perez@dqcm.uhu.es; mcnica@dqcm.uhu.es
Received October 22, 2005
ABSTRACT
The complex
{[HC(3,5-Me2pz)3]Cu(NCMe)}BF4 catalyzes the transfer of the :CHCO2Et unit from ethyl diazoacetate to several saturated and
unsaturated substrates with very high yields and under biphasic conditions using the ionic liquid [bmim][PF6] and hexane as the reaction
medium. The catalyst has been tested for several cycles of recovery and reuse without any loss of activity.
Diazo compounds have been extensively employed as a
carbene source in organic synthesis.1 This methodology has
gainered increasing interest in the past decade because of
the use of transition-metal-based catalysts to promote and
control the transfer of the CR1R2 unit to a plethora of organic
substrates (Scheme 1). However, most of these catalytic
systems operate under homogeneous conditions. The recov-
ery and subsequent reuse of the catalysts are of interest to
minimize cost in scale-up processes.2 Despite the potential
wide range of reactions involving metal-catalyzed diazo
compound decomposition, only a few systems allow for the
separation of the catalyst. For example, anchoring of the
catalytic species to a solid support, such as silica,3 clays,
zeolites,4 and polymeric materials,5 has the potential for
multiple catalytic sites instead of the characteristic single-
site catalysis observed in the homogeneous phase. Only
recently, Davies et al. have described an effective strategy
for the immobilization of dirhodium dimer catalysts for
carbene transfer from diazo compounds.6 In the past decade,
biphasic catalysis has emerged as a useful technique for
(3) See, for example: (a) Lemaire, M. Pure Appl. Chem. 2004, 76, 679.
(b) Lancaster, T. M.; Lee, S. S.; Ying, J. Y. Chem. Commun. 2005, 3577.
(c) Sacco, L.; Lambert, S.; Pirard, J. P.; Noels, A. F. J. Catal. 2005, 232,
51.(d) Kantam, M. L.; Haritha, Y.; Reddy, N. M.; Choudary, B. M.;
Figueras, F. Catal. Lett. 2002, 83, 187.
(4) See, for example: (a) Fraile, J. M.; Garcia, J. I.; Herrerias, C. I.;
Mayoral, J. A.; Reiser, O.; Socuellamos, A.; Werner, H. Chem.-Eur. J.
2004, 10, 2997. (b) Cornejo, A.; Fraile, J. M.; Garcia, J. I.; Gil, M. J.;
Herrerias, C. I.; Legarreta, G.; Martinez-Merino, V.; Mayoral, J. A. J. Mol.
Catal. A 2003, 196, 101. (c) Zhang, J.-L.; Liu, Y.-L.; Che, C.-M. Chem.
Commun. 2002, 2906. (d) Fraile, J. M.; Garcia, J. I.; Mayoral, J. A.; Tarnai,
T. Tetrahedron: Asymmetry 1998, 9, 3997.
(5) (a) Doyle, M. P.; Yan, M.; Gau, H.-M.; Blossey, E. C. Org. Lett.
2003, 5, 561. (b) Doyle, M. P.; Timmons, D. J.; Tumonis, J. S.; Gau, H.-
M.; Blossey, E. C. Organometallics 2002, 21, 1747. (c) Burguete, M. I.;
Fraile, J. M.; Garc´ıa, J. I.; Garc´ıa-Verdugo, E.; Luis, S. V.; Mayoral, J. A.
Org. Lett. 2000, 2, 3905.
(1) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; John Wiley & Sons: New
York, 1998.
(2) (a) Song, C. E.; Lee, S. G. Chem. ReV. 2002, 102, 3495. (b) Bian, Q.
H.; Qiao, Z.; Hou, S. C.; Wang, X.; Wang, M. Chin. J. Chem. 2004, 24,
831.
10.1021/ol052564j CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/27/2006

easy separation and recycling of catalysts with behaviors
similar to that observed under homogeneous conditions. An
earlier report from this laboratory16 showed that fixation of
those catalysts on silica gel was feasible. However, their use
in the olefin cyclopropanation reaction demonstrated that the
selectivity was different from that of the homogeneous
system. These results prompted us to move into biphasic
catalysis and specifically into the use of ILs as the reaction
medium for the copper-induced decomposition of EDA and
the subsequent carbene transfer to several substrates. We
chose the readily available [bmim][PF6]17 ionic liquid as the
reaction medium. As expected, the neutral TpxCuL com-
plexes did not dissolve in this IL. On the other hand, the
related cationic complex {[HC(3,5-Me2pz)3]Cu(NCMe)}BF4
(1) (Figure 1), reported by Reger and co-workers,18 was
Scheme 1. Common Transition-Metal-Catalyzed Carbene
Transfer Reactions from Diazo Compounds
effecting heterogeneous and homogeneous catalysis. Biphasic
catalysis is currently based mainly in the use of fluorous
chemistry7 and ionic liquids (IL),8 and its use for the catalytic
decomposition of diazocompounds has still been limited to
the olefin cyclopropanation reaction.9
In recent years, we have developed a family of copper-
based catalysts of the general formula TpxCuL (Tpx )
homoscorpionate ligand)10 for the transfer of the :CHCO2Et
fragment from ethyl diazoacetate (EDA) to a variety of
saturated (N-H,11 O-H,12 and C-H13 bonds) and unsatur-
ated (alkenes14 and alkynes15) substrates under homogeneous
conditions. We have now designed a catalytic system for
Figure 1. {[HC(3,5-Me2pz)3]Cu(NCMe)}BF4 (1).
(6) (a) Davies, H. M. L.; Walji, A. M. Org. Lett. 2005, 7, 2941. (b)
Davies, H. M. L.; Walji, A. M.; Nagashima, T. J. Am. Chem. Soc. 2004,
126, 4271. (c) Davies, H. M. L.; Walji, A. M. Org. Lett. 2003, 5, 479. (d)
Nagashima, T.; Davies, H. M. L. Org. Lett. 2002, 4, 1989.
(7) (a) Dobbs, A. P.; Kimberley, M. R. J. Fluorine Chem. 2002, 118, 3.
(b) Gladysz, J. A.; Curran, D. P. Tetrahedron 2002, 58, 3823.
(8) (a) Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39,
3772. (b) Earle, M. J.; Seddon, K. R. Pure Appl. Chem. 2000, 72, 1391. (c)
Welton, T. Chem. ReV. 1999, 99, 2071.
(9) (a) Davies, D. L.; Kandola, S. K.; Patel, R. K. Tetrahedron:
Asymmetry 2004, 15, 77. (b) Fraile, J. M.; Garc´ıa, J. I.; Herrer´ıas, C. I.;
Mayoral, J. M.; Reiser, O.; Vaultier, M. Tetrahedron Lett. 2004, 45, 6765.
(c) Fraile, J. M.; Garc´ıa, J. I.; Herrer´ıas, C. I.; Mayoral, J. M.; Gmough, S.;
Vaultier, M. Green Chem. 2004, 6, 93. (d) Yadav, J. S.; Reddy, B. V. S.;
Reddy, P. N. AdV. Synth. Catal. 2004, 346, 53. (e) Chandrasekhar, S.;
Narasihmulu, Ch.; Jagadeshwar, V.; Reddy, K. V. Tetrahedron Lett. 2003,
44, 3629. (f) Iwasa, S.; Tsushima, S.; Nishiyama, K.; Tsuchiya, Y.;
Takezawa, F.; Nishiyama, H. Tetrahedron: Asymmetry 2003, 14, 855. (g)
Yang, F.; Zhang, Y.-M-; Qiu, W.-W.; Tang, J.; He, M.-Y. Chin. J. Chem.
2002, 20, 114. (h) Fraile, J. M.; Garc´ıa, J. I.; Herrer´ıas, C. I.; Mayoral, J.
M.; Carrie´, D.; Vaultier, M. Tetrahedron Lett. 2001, 12, 1891.
(10) Trofimenko, S. Scorpionates, The Coordination Chemistry of
Polypyrazolylborate Ligands; Imperial College Press: London, 1999.
(11) Morilla, M. E.; D´ıaz-Requejo, M. M.; Belderrain, T. R.; Nicasio,
M. C.; Trofimenko, S.; Pe´rez, P. J. Chem. Commun. 2002, 2998.
(12) Morilla, M. E.; Molina, M. J.; D´ıaz-Requejo, M. M.; Belderrain,
T. R.; Nicasio, M. C.; Trofimenko, S.; Pe´rez, P. J. Organometallics 2004,
23, 2914.
soluble in [bmim][PF6]. To establish the catalytic properties
of 1 under homogeneous conditions, for EDA decomposition,
a first set of experiments was carried out on the following
substrates: styrene, 1-phenyl-1-propyne, aniline, ethanol, and
cyclohexane. In a typical experiment, 1 mmol of EDA was
slowly added (6 h) to a solution containing 1 (5% with
respect to EDA) and the corresponding substrate in excess.
After the addition, no EDA was observed by GC. As shown
in Table 1, the additions to double and triple bonds were
achieved with high yields (entries 1 and 2), a feature also
observed for insertion into N-H and O-H bonds (entries 3
and 4). These results are similar to those obtained with the
Tpx-containing catalysts.11,12,14,15 Insertion into the C-H
bonds of cyclohexane was also observed, albeit in low yield
(30%). The catalytic activity of complex 1 was noteworthy
with respect to copper-based catalysts that promote the olefin
cyclopropanation reaction with EDA because few catalytic
copper systems perform alkyne cyclopropenation15 and X-H
functionalization (X ) N, H, C).11-13
(13) (a) D´ıaz-Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.;
Trofimenko, S.; Pe´rez, P. J. J. Am. Chem. Soc. 2002, 124, 896. (b) Caballero,
A.; D´ıaz-Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.; Trofimenko,
S.; Pe´rez, P. J. J. Am. Chem. Soc. 2003, 125, 1446. (c) Caballero, A.; D´ıaz-
Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.; Trofimenko, S.; Pe´rez,
P. J. Organometallics 2003, 22, 4145.
(14) (a) D´ıaz-Requejo, M. M.; Belderrain, T. R.; Trofimenko, S.; Pe´rez,
P. J. J. Am. Chem. Soc. 2001, 123, 3167. (b) D´ıaz-Requejo, M. M.;
Caballero, A.; Belderrain, T. R.; Trofimenko, S.; Pe´rez, P. J. J. Am. Chem.
Soc. 2002, 124, 978.
Once the catalytic properties of complex 1 were demon-
strated, we tested it under biphasic conditions using [bmim]-
(16) D´ıaz-Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.; Pe´rez,
Organometallics 2000, 19, 285.
(17) (a) Wilkes, J. S.; Levisky, J. A.; Wilson, R. A.; Hussey, C. L. Inorg.
Chem. 1982, 21, 1263. (b) Suarez, P. A. Z.; Dullius, J. E. L.; Einloft, S.;
de Souza, R. F.; Dupont, J. Polyhedron 1996, 15, 1217.
(18) Reger, D. L.; Collins, J. E.; Rheingold, A. L.; Liable-Sands, L. M.
Organometallics 1996, 15, 2029.
(15) D´ıaz-Requejo, M. M.; Mairena, M. A.; Belderrain, T. R.; Trofi-
menko, S.; Pe´rez, P. J. Chem. Commun. 2001, 1804.
558
Org. Lett., Vol. 8, No. 4, 2006

Table 1. Carbene Transfer from Ethyl Diazoacetate (EDA)
Using {[HC(3,5-Me2pz)3]Cu(NCMe)}PF6 (1) as the Catalyst in
Homogeneous (Methylene Chloride) and Biphasic
([bmim][PF6]-hexane) Mediaa
Table 2. Recycling of 1-[bmim]PF6 for the Reaction of Ethyl
Diazoacetate with Styrene, Aniline, and Ethanola
styrene
aniline
ethanol
run
conversion
cis:trans
conversion
conversion
1
2
3
4
5
95
96
95
98
98
59:41
57:43
60:40
55:45
61:39
96
93
94
95
95
98
98
97
95
95
a Experiments carried out as those shown in Table 1.
styrene cyclopropanation, the diastereoselectivity was con-
sistent throughout the cycles. The recovered IL catalyst phase
was stored under nitrogen at 0 °C for several weeks and then
employed for a series of experiments with the substrates in
Table 1 without any significant loss of activity. In contrast,
reported systems for styrene cyclopropanation in an IL have
exhibited a decrease of the catalytic activity after 2-3 cycles.
Bisoxazoline copper catalysts have been employed under
biphasic conditions. Work by Davies et al.9a with these
catalysts has shown that the cyclopropanation of styrene with
EDA was achieved in five cycles with bmim and different
counterions. The yields dropped from the initial 88 to 69%
in the fifth cycle and to 51% in the eighth run. Mayoral and
co-workers9b,c,h have also developed the use of such catalysts
in ILs. However, the maximum yields, at the first run, were
around 50-60% for the same reaction (EDA + styrene) and
the conversions decreased in the following runs. Better yields
were reported by Yadav et al.9d with rhodium-based catalysts,
with 88% conversion in the first run dropping to 69% in the
fifth run. As in the case of Ru-containing catalysts,9f yields
varied from 62 to 13% during the five cycles. The degree of
conversion observed in our system was better than that
previously described in styrene cyclopropanation systems.
Conversion and selectivity were nearly identical in both
media: in the case of the styrene cyclopropanation, the cis/
trans ratio in the homogeneous case (52:48) was similar to
that found using the IL system (59:41).
Complex 1 was a good catalyst for the decomposition of
ethyl diazoacetate and subsequent carbene transfer to satu-
rated and unsaturated substrates in both homogeneous and
biphasic conditions. The study of the effect of different
groups attached to the pyrazolyl rings on the catalytic
behavior of 1 is merited because diazo decomposition seems
to be related to the electrophilic nature of the metal center.1
Electrophile-nucleophile couples may be considered for the
interactions between the catalyst MLn and EDA in the
transient metallocarbene intermediate and during reaction
with the substrate. An increase in the electrophilic character
at the metal center usually leads to a more active catalyst.
Such attributes can be measured, to a certain extent, using
the ν(CO) frequencies of the carbonyl adducts. A compari-
son18 between the complexes Tp*Cu(CO) and {[HC(3,5-Me2-
pz)3]Cu(CO)}BF4 shows a difference of ca. 50 wavenumbers,
the latter appearing at a higher frequency (2066 vs 2113
cm-1). Back-donation from the metal center resulted in lower
a Reactions performed at room temperature with 0.05 mmol of the
catalyst, 5% with respect to EDA. b Based on EDA. Diethyl fumarate and
maleate and ethyl glycolate accounted for the remaining diazo compound.
Determined by NMR of the reaction mixture with an internal standard.
PF6. The catalyst was dissolved in the ionic liquid (1.5 g),
and 4 mL of hexane was added along with the substrate.
From a syringe pump, EDA (1 mmol dissolved in hexane)
was added for 6 h. After that time, the organic phase was
transferred, and the ionic liquid was washed twice with
hexane. Then, the products were detected and conversions
were quantified by NMR. The mass balance (based on EDA)
demonstrated that no products remained in the IL. To check
if any significant catalyst leaching into the organic phase
took place, a second 1 mmol portion of EDA was added to
the organic solution in one portion, and the mixture was
stirred for 6 h. No EDA consumption was observed, evidence
that the amount of active catalyst in the organic solution was
negligible. To our best knowledge, the examples reported
herein concerning alkyne cyclopropenation as well as the
functionalization of N-H, O-H, and C-H bonds by carbene
insertion are unprecedented in this reaction medium. As
mentioned above, only the cyclopropanation of olefins, with
diazo compounds, has been reported in IL, either with
copper-,9a-c,h ruthenium-,9f palladium-,9g or rhodium-based9d
catalysts, although the conversions obtained with this
1-[bmim]PF6 system are higher than those obtained with
those catalysts.
We concluded that this biphasic catalytic system operated
similarly to the homogeneous systems, without significant
catalyst leaching. Reuse of the catalyst was demonstrated
next in five consecutive experiments using the recovered IL
solution containing 1 and one of three different substrates:
styrene, aniline, and ethanol. In each case, after the addition
of EDA, the organic phase was separated and the IL was
washed with more hexane prior to the next loading with more
substrate and EDA. The results are shown in Table 2.
Conversions were maintained for five cycles within the range
93-98% without any deactivation of the catalyst. For the
Org. Lett., Vol. 8, No. 4, 2006
559

electron density and may explain 1 to functionalize cyclo-
hexane with EDA. Although the corresponding Tp* catalyst
does not induce such transformations,13c the functionalization
of cyclohexane with the complexes TpMsCu and TpBr3Cu-
(NCMe) has been reported13a,b in higher yields than that now
found with 1 (despite lower ν(CO) values observed for
TpMsCu(CO) and TpBr3Cu(CO): 2079 and 2105 cm-1,
respectively). Future development of active catalysts based
on the use of trispyrazolylmethane ligands for C-H bond
functionalization may require other attributes to enhance
conversion. The cationic nature of this new family of
catalysts does provide efficiency under biphasic conditions.
In conclusion, we have demonstrated the catalytic capa-
bilities of the complex {[HC(3,5-Me2pz)3]Cu(NCMe)}BF4
for the transfer of the :CHCO2Et in homogeneous and
biphasic media. The use of this methodology in ionic liquids
for alkyne cyclopropenation as well as for N-H, O-H, and
C-H insertion is unprecedented and makes this complex a
promising catalyst for the carbene transfer reaction.
Acknowledgment. Dedicated to Dr. Jose Antonio Abad
on the occasion of his regretted retirement. We thank the
MEC for financial support (Proyecto BQU2002-01114). A.C.
thanks the MEC for a research fellowship, and M.M.D.R.
thanks the Ramon y Cajal Program (MEC) for financial
support.
Supporting Information Available: Experimental details
of the catalytic experiments (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
OL052564J
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Org. Lett., Vol. 8, No. 4, 2006