Simple and efficient heterogeneous copper catalysts for enantioselective C-H carbene insertion

Article abstract of DOI:10.1021/ol070092y

Immobilized box-Cu complexes are able to efficiently catalyze the insertion of a carbene, from methyl phenyldiazoacetate, into C-H bonds of THF, with high enantioselectivity (up to 88% ee). The immobilization not only allows recovery and reuse of the enan

Full text of DOI:10.1021/ol070092y

ORGANIC
LETTERS
2
007
Vol. 9, No. 4
31-733
Simple and Efficient Heterogeneous
Copper Catalysts for Enantioselective
7
C−H Carbene Insertion
Jos e´ M. Fraile,* Jos e´ I. Garc ´ı a, Jos e´ A. Mayoral,* and Marta Rold a´ n
Departamento de Qu ´ı mica Org a´ nica, Instituto de Ciencia de Materiales de Arag o´ n
and Instituto UniVersitario de Cat a´ lisis Homog e´ nea, UniVersidad de
Zaragoza-C.S.I.C., E-50009 Zaragoza, Spain
jmfraile@unizar.es; mayoral@unizar.es
Received January 12, 2007
ABSTRACT
Immobilized box−Cu complexes are able to efficiently catalyze the insertion of a carbene, from methyl phenyldiazoacetate, into C−H bonds of
THF, with high enantioselectivity (up to 88% ee). The immobilization not only allows recovery and reuse of the enantioselective catalyst but
also provides an improvement in the selectivities from the values obtained in solution, probably due to a confinement effect of the bidimensional
support.
Functionalization of C-H bonds is currently an important
field of research in chemistry. Whereas catalytic oxidative
addition is still challenging, the metal-catalyzed insertion of
carbenes, generated from diazo compounds, is a well-
established alternative method to functionalize C-H bonds.
Rhodium catalysts have proven to be the most efficient for
that for the first time the cheap and easily accessible bis-
(oxazoline)-copper complexes can act as efficient catalysts
for this type of reaction provided they are immobilized onto
a bidimensional clay by simple cationic exchange.
1
Four different ligand families were chosen for this study
7
(Figure 1): the C -symmetric bis(oxazoline) (box, 1) and
2
8
the asymmetric version of this reaction, mainly the intramo-
azabis(oxazoline) (azabox, 2) ligands and the nonsymmetric
quinolineoxazoline (quox, 3) system. All of these ligands
2
9
lecular variant, and this approach has been extended in
3
recent years to intermolecular reactions. In contrast, copper
are known to form copper complexes that efficiently catalyze
catalysts have hardly been used for this type of reaction. Only
in the past few years did P e´ rez and co-workers show that
trispyrazolylborate complexes of copper, silver, and gold are
active and selective in the intermolecular insertion of
(4) Examples of carbene insertions in aliphatic C-H bonds: (a) Urbano,
J.; Belderra ´ı n, T. R.; Nicasio, M. C.; Trofimenko, S.; D ´ı az-Requejo, M.
M.; P e´ rez, P. J. Organometallics 2005, 24, 1528-1532. (b) Caballero, A.;
D ´ı az-Requejo, M. M.; Belderra ´ı n, T. R.; Nicasio, M. C.; Trofimenko, S.;
P e´ rez, P. J. Am. Chem. Soc. 2003, 125, 1446-1447. (c) Caballero, A.; D ´ı az-
Requejo, M. M.; Belderra ´ı n, T. R.; Nicasio, M. C.; Trofimenko, S.; P e´ rez,
P. Organometallics 2003, 22, 4145-4150. For other carbene insertions,
see: (d) D ´ı az-Requejo, M. M.; P e´ rez, P. J. J. Organomet. Chem. 2005,
4
carbenes. Regarding the asymmetric insertion reactions,
copper catalysts have only been successful in the intramo-
5
,6
lecular version. In this communication, we demonstrate
6
90, 5441-5450 and references cited therein.
(
5) Some examples: (a) Wee, A. G. H. J. Org. Chem. 2001, 66, 8513-
(
(
1) Ye, T.; McKervey, M. A. Chem. ReV. 1994, 94, 1091-1160.
2) Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861-
8517. (b) Doyle, M. P.; Phillips, I. M. Tetrahedron Lett. 2001, 42, 3155-
3158. (c) Doyle, M. P.; Hu, W. J. Org. Chem. 2000, 65, 8839-8847. (d)
Lim, H.-J.; Sulikowski, G. A. J. Org. Chem. 1995, 60, 2326-2327.
(6) Recently, an enantioselective copper-catalyzed intramolecular O-H
insertion has been described: Maier, T. C.; Fu, G. C. J. Am. Chem. Soc.
2006, 128, 4594-4595.
2
903.
(
3) (a) Davies, H. M. L. Angew. Chem., Int. Ed. 2006, 45, 6422-6425.
b) Davies, H. M. L.; Nikolai, J. Org. Biomol. Chem. 2005, 3, 4176-
187.
(
4
1
0.1021/ol070092y CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/27/2007

Table 1. Results of the Reactions between Methyl
Phenyldiazoacetate and THF Catalyzed by Homogeneous
Copper Complexesa
b
ligand
conversion (%)
syn/anti
% ee syn
% ee anti
-
41
48
49
48
85
39
20
54
74
44
75:25
64:36
71:29
71:29
64:36
60:40
77:23
74:26
56:44
72:28
-
59
2
14
59
57
2
1
64
6
-
40
6
27
55
40
4
12
48
6
1a
1
1
b
d
2a
2a
2a
c
d
2b
Figure 1. Ligands used for enantioselective C-H carbene insertion.
2c
3a
a
the cyclopropanation of alkenes with diazo compounds and
therefore were good candidates for the insertion reaction.
Different copper salts were tested in the homogeneous
Reaction conditions: 2% Cu(OTf)2, 2.2% ligand, THF as solvent, slow
addition (2 h) of diazo compound, reflux. Conversion and diastereoselectivity
were determined by gas chromatography. Enantioselectivities were deter-
mined by HPLC (Chiralcel OD-H). The major syn isomer has the absolute
configuration 2R,RS, from the sign of the optical rotation (ref 11).
Conversion to insertion products. As total conversion of the diazo compound
was observed in all cases, this value reflects the chemoselectivity to the
b
phase: Cu(OTf)
prepared from CuCl and AgSbF
clearly better than the chloride, bromide, and acetate, as also
2
, CuBr
2
, Cu(OAc)
2 6
, CuCl, and CuSbF
(
6
). Copper triflate was
c
insertion reaction. Reaction carried out at room temperature with 4%
catalyst. d Reaction carried out in hexane under reflux with 2 equiv of THF.
1
0
occurs in cyclopropanation reactions, and CuSbF
show any significant improvement. Cu(OTf) was therefore
used due to its ease of handling. Catalysts were tested in the
6
did not
2
11
insertion of methyl phenyldiazoacetate in THF under reflux
Scheme 1), and the results of the homogeneous reactions
ligand (2a). Regarding enantioselectivity, only symmetrical
ligands are efficient and both box and azabox ligands with
the same substituents lead to a similar enantiomeric excess.
Phenyl or isopropyl substituents show higher enantioselec-
tivity, around 60% ee, than tert-butylsa situation in contrast
with the behavior of the same ligands in the related
cyclopropanation reaction. However, one drawback of these
systems is the lower diastereoselectivity, which is associated
with the higher enantioselectivity. These results are slightly
(
are gathered in Table 1.
Scheme 1. Reaction between Methyl Phenyldiazoacetate and
THF
worse than those obtained with Rh
same conditions (2:1 diastereomeric ratio, 72% ee syn),
2 4
(S-DOSP) under the
11
and we tried to improve the enantioselectivity of ligand 2a
by using the same strategies, i.e., lowering the temperature
or using hexane as solvent. At room temperature, the yield
was lower and the enantioselectivity was not improved. The
use of hexane was very detrimental, in terms of both yield
and enantioselectivity, probably due to the low solubility of
the 2a-Cu complex. The stereochemical course of the
insertion of carbene with copper catalysts cannot be outlined,
as the reaction mechanism is still poorly understood.
As can be seen, all the catalysts, including copper triflate
itself, are active in this reaction, with yields in the range
40-50%. However, azabox ligands (2) are clearly superior,
even leading to 85% in the case of the phenyl-substituted
There are very few examples in the literature concerning
the use of heterogeneous catalysts for the enantioselective
insertion of carbenes into C-H bonds. The best homoge-
(
7) (a) Gosh, A. K.; Mathivanan, P.; Capiello, J. Tetrahedron: Asymmetry
1
998, 9, 1-45. (b) Jørgensen, K. A.; Johannsen, M.; Yao, S. L.; Audrain,
H.; Thorhauge, J. Acc. Chem. Res. 1999, 32, 605-613. (c) Pfaltz, A. Synlett
12
1
3
999, 835-842. (d) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000,
3, 325-335. (e) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M.
neous catalysts in our tests were selected for immobilization
Chem. ReV. 2000, 100, 2159-2231. (f) Desimoni, G.; Faita, G.; Jørgensen,
13
onto laponite clay by cationic exchange in methanol. The
K. A. Chem. ReV. 2006, 106, 3561-3651.
heterogeneous catalysts were used under the same conditions
as the homogeneous ones. The reactions were truly hetero-
geneous, as shown by filtration experiments, and leaching
of copper was not detected by ICP analysis.
(
8) (a) Glos, M.; Reiser, O. Org. Lett. 2000, 2, 2045-2048. (b) Werner,
H.; Vicha, R.; Gissibl, A.; Reiser, O. J. Org. Chem. 2003, 68, 10166-
0168.
1
(9) (a) Chelucci, G.; Gladiali, S.; Saba, A. Tetrahedron: Asymmetry 1999,
1
0, 1393-1400. (b) Wu, X.-Y.; Li, X.-H.; Zhou, Q.-L. Tetrahedron:
Asymmetry 1998, 9, 4143-4150.
(10) (a) Fraile, J. M.; Garc ´ı a, J. I.; Gil, M. J.; Mart ´ı nez-Merino, V.;
Mayoral, J. A.; Salvatella, L. Chem.-Eur. J. 2004, 10, 758-765. (b) Fraile,
(12) Davies, H. M. L.; Walji, A. M. Org. Lett. 2003, 5, 479-482.
(13) (a) Fraile, J. M.; Garc ´ı a, J. I.; Herrer ´ı as, C. I.; Mayoral, J. A.; Reiser,
O.; Socu e´ llamos, A.; Werner, H. Chem.-Eur. J. 2004, 10, 2997-3005.
(b) Fraile, J. M.; Garc ´ı a, J. I.; Herrer ´ı as, C. I.; Mayoral, J. A.; Harmer, M.
A. J. Catal. 2004, 221, 532-540.
J. M.; Garc ´ı a, J. I.; Mayoral, J. A.; Tarnai, T. J. Mol. Catal. A 1999, 144,
8
5-89.
(
11) Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc.
2
000, 122, 3063-3070.
732
Org. Lett., Vol. 9, No. 4, 2007

Azabox ligands form very stable complexes, which allows
an efficient immobilization by electrostatic interactions.
geneous results (61% ee and 64:36 dr). Moreover, this
catalyst is also recoverable and can be used three more times
with the same results, thus demonstrating the stability of the
1a-Cu complex. In fact, after four runs, each catalytic
center of the 1a-Cu-laponite catalyst has converted 137
molecules of THF to the products, with an average enanti-
oselectivity of 82.5% ee for the syn isomers.
1
3a
In this case, ligands 2a-c lead to results very similar to those
in solution, with the important practical advantage of being
fully recoverable at least twice. Surprisingly, the immobiliza-
tion of 3a produces a significant increase in the enantiose-
lectivity, from virtually zero to values in the region of 40%
ee (Table 2). This result represents a new example of a
1
3
This enhancement in the selectivities is again in agreement
with our previous results, as this same ligand showed the
largest confinement effect in the case of cyclopropanation
1
4b,15
reactions.
We previously showed that surface effects
Table 2. Results of the Reaction between Methyl
Phenyldiazoacetate and THF Catalyzed by Laponite-Supported
Copper Complexesa
were due to the close proximity of the catalytic complex,
and this proximity can be increased by using solvents with
14
low dielectric constants. In view of this, we tried to enhance
the surface effect by carrying out the reaction in hexane.
The detrimental effect of solvent on the yield was less
marked than in the case of the homogeneous catalysts, with
only marginal reductions. The enantioselectivity was slightly
better in all cases. The most relevant effect was observed
with azabox 2a, leading to 71% ee in comparison with 58%
ee obtained in THF. Box 1a gave the highest enantiomeric
excess, 88% ee in the first reaction.
b
ligand run conversion (%) syn/anti % ee syn % ee anti
-
1
1
2
3
4
5
1
2
1
2
3
1
2
3
1
1
2
3
1
2
1
2
21
66
71
72
65
37
59
40
60
55
61
43
42
44
27
50
56
62
31
44
35
30
52:48
75:25
77:23
75:25
72:28
54:46
78:22
74:26
74:26
74:26
73:27
71:29
71:29
71:29
51:49
59:41
58:42
56:44
60:40
60:40
62:38
64:36
-
84
83
82
81
28
88
85
58
57
56
71
66
66
2
62
61
58
30
41
44
45
-
39
40
39
40
24
46
46
51
51
54
56
53
56
16
59
59
56
0
1a
ac
1
2
a
In conclusion, readily accessible Cu(II) complexes easily
immobilized on a cheap support promote insertion of
carbenes into C-H bonds, with enantioselectivities up to
2
ac
88% ee. This result demonstrates not only how immobiliza-
tion is a method to recover and reuse the catalyst but also
how the appropriate selection of support, immobilization
method, and chiral catalyst enables an improvement in the
catalytic performance, in terms of both yield and enantiose-
lectivity. New experiments are underway to expand the scope
of the reaction and to study its stereochemical course.
2b
2c
3
3
a
2
9
8
ac
Acknowledgment. This work was made possible by the
generous financial support of the CICYT (projects CTQ2005-
08016 and Consolider Ingenio 2010 CSD2006-0003). M.R.
is indebted to the Diputaci o´ n General de Arag o´ n for a grant.
a
Reaction conditions: 2% catalyst, THF as solvent, slow addition (2
h) of diazo compound, reflux. Conversion and diastereoselectivity were
determined by gas chromatography. Enantioselectivities were determined
by HPLC (Chiralcel OD-H). The major syn isomer has the absolute
configuration 2R,RS, from the sign of the optical rotation (ref 11).
Conversion to insertion products. As total conversion of the diazo compound
was observed in all cases, this value reflects the chemoselectivity to the
Supporting Information Available: Full characterization
of ligands, reagent, and products, catalytic reactions, and
chromatographic methods. This material is available free of
charge via the Internet at http://pubs.acs.org.
b
c
insertion reaction. Reaction carried out in hexane under reflux with 2
equiv of THF.
OL070092Y
(
14) (a) Cornejo, A.; Fraile, J. M.; Garc ´ı a, J. I.; Gil, M. J.; Herrer ´ı as, C.
I.; Legarreta, G.; Mart ´ı nez-Merino, V.; Mayoral, J. A. J. Mol. Catal. A
003, 196, 101-108. (b) Fern a´ ndez, A. I.; Fraile, J. M.; Garc ´ı a, J. I.;
Herrer ´ı as, C. I.; Mayoral, J. A.; Salvatella, L. Catal. Commun. 2001, 2,
65-170.
15) Castillo, M. R.; Fousse, L.; Fraile, J. M.; Garc ´ı a, J. I.; Mayoral, J.
A. Chem.-Eur. J. 2007, 13, 287-291.
surface effect, which has already been observed in cyclo-
propanation reactions.
14,15
2
The best results were obtained with box 1a. The im-
mobilized catalyst gave rise to 84% ee with a diastereomeric
ratio of 75:25, a significant improvement from the homo-
1
(
Org. Lett., Vol. 9, No. 4, 2007
733