A fluorous chiral dirhodium(II) complex as a recyclable asymmetric catalyst

Article abstract of DOI:10.1021/ol050486u

(Chemical Equation Presented) The chiral fluorous complex tetrakis-dirhodium(II)-(S)-N-(n-perfluorooctylsulfonyl)prolinate has been prepared and used as a catalyst in homogeneous or fluorous biphasic fashion. The catalyst displays good chemo- and enantios

Full text of DOI:10.1021/ol050486u

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1841-1844
A Fluorous Chiral Dirhodium(II) Complex
as a Recyclable Asymmetric Catalyst
Andrea Biffis,* Mirko Braga, Sara Cadamuro, Cristina Tubaro, and Marino Basato
Dipartimento di Scienze Chimiche, UniVersita` di PadoVa, Via Marzolo 1,
I-35131 PadoVa, Italy
andrea.biffis@unipd.it
Received March 7, 2005
ABSTRACT
The chiral fluorous complex tetrakis-dirhodium(II)
homogeneous or fluorous biphasic fashion. The catalyst displays good chemo- and enantioselectivity in intermolecular cyclopropanation and
H bond activation reactions. The catalyst can be simply and thoroughly separated from the reaction mixture and is recyclable.
−(S)-N-(n-perfluorooctylsulfonyl)prolinate has been prepared and used as a catalyst in
C
−
The synthetic potential of dimeric rhodium(II) complexes
as catalysts for organic syntheses, most notably those
involving diazocompounds, has been widely recognized in
the course of the last 15 years.1 There is an impressive variety
of chemical transformations that can be mediated by such
compounds through the formation of highly reactive metal
carbene intermediates, including cyclopropanations, inser-
tions into C-H, C-C, and heteroatom-H bonds, ylide
formations, and dipolar cycloaddition reactions; efficient
asymmetric variants of many of these reactions have been
developed as well.1,2 Among the complexes that have
emerged as most useful for asymmetric transformation, the
dirhodium(II) carboxylates of amino acid derivatives of type
1 introduced by Hashimoto and Ikegami,3 the dirhodium(II)
carboxyamidates of type 2 developed by Doyle,4 and finally
the dirhodium(II) prolinates of type 3 first reported by
McKervey5 and later extensively studied by Davies6-8 need
Figure 1.
special mention (Figure 1). In particular, the latter type of
catalyst exhibits some outstanding properties such as a high
enantio- and diastereoselectivity in cyclopropanations involv-
ing aryl- or vinyl diazoacetates7 as well as a high chemo-
and stereoselectivity in intermolecular C-H insertion reac-
tions.8 Despite the potential of these catalysts, one of the
(1) (a) Merlic, C. A.; Zechman, A. L. Synthesis 2003, 1137. (b) Doyle,
M. P.; Ren, T. Prog. Inorg. Chem. 2001, 49, 113. (c) Doyle, M. P.;
McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis
with Diazo Compounds; Wiley: New York, 1998.
(2) (a) Forbes, D. C.; McMills, M. C. Curr. Org. Chem. 2001, 5, 1091.
(b) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911.
(3) Hashimoto, S.; Watanabe, N.; Ikegami, S. Tetrahedron Lett. 1990,
31, 5173.
(4) Doyle, M. P.; Brandes, B. D.; Kazala, A. P.; Pieters, R. J.; Jarstfer,
M. B.; Watkins, L. M.; Eagle, C. T. Tetrahedron Lett. 1990, 31, 6613.
(5) Kennedy, M.; McKervey, M. A.; Maguire, A. R.; Roos, G. H. P. J.
Chem. Soc., Chem. Commun. 1990, 361.
10.1021/ol050486u CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/07/2005

fundamental problems for their industrial application is the
need for efficient catalyst recovery and recycling, which
arises from the relatively large quantity of catalyst (1 mol
%) usually needed for these reactions. In this connection,
there have already been some successful attempts to hetero-
genize chiral dirhodium(II) catalysts on solid supports
through covalent linkages9 or monocoordination to one apical
position of the catalyst.10 We report in this paper on a novel
dirhodium(II) prolinate catalyst bearing perfluoroalkyl chains.
Such functionalization allows an easy recovery of the catalyst
from the reaction mixture by confining it into a separated,
perfluorinated liquid phase (Fluorous Biphasic Catalysis,
FBS)11 or solid phase (Bonded Fluorous Phase Catalysis,
BFPC)12,13 or by extracting it into a perfluorinated phase at
the end of the reaction.
Scheme 1
The catalyst tetrakis-dirhodium(II)-(S)-N-(n-perfluoro-
octylsulfonyl)prolinate 4 has been prepared from L-proline
benzyl ester hydrochloride in three steps following the
reaction pathway outlined in Scheme 1. We have extensively
tried to avoid protection of the carboxylate function, without
success: simple proline does not react with the sulfonyl
fluoride under any of the conditions we have employed.
Catalytic tests have been performed on a standard asym-
metric cyclopropanation reaction with styrene and methyl
phenyldiazoacetate as the reagents. Reaction conditions
derived from the work of Davies15 (10 equiv of styrene, 1
equiv of diazocompound, 0.01 equiv of catalyst, room
temperature, controlled diazocompound addition over 30
min) have been employed (see also Supporting Information).
The results are reported in Table 1.
Complex 4 has a weight percentage of fluorine of 50%.
Although as a rule of thumb suitable catalysts for fluorous
biphasic catalysis should contain a weight percentage of
fluorine of at least 60%,11b-d several metal complexes have
already been reported that exhibit good performance at lower
fluorine content (see Chapter 6 in ref 11a). Indeed, 4 shows
high affinity for a fluorous phase, both solid and liquid (vide
infra). For example, it can be conveniently heterogenized
on a solid support functionalized with perfluoroalkyl chains
by simple addition of the support to a toluene or dichloro-
methane solution of the complex. Quantitative adsorption
of 4 from the organic solution occurs using as support a
fluorous reversed-phase silica prepared by surface function-
alization with 1H,1H,2H,2H-pefluorodecyldimethylchloro-
silane,14 which we have already successfully employed for
the heterogenization of dirhodium(II) perfluorocarboxylate
complexes;12 such bonded fluorous phase (BFP)-supported
catalyst will be hereafter termed as BFP-4.
Initial tests were run under homogeneous conditions in
dichloromethane solution (entries 1-4). As expected from
Table 1. Asymmetric Cyclopropanation Reactions with
Homogeneous and Supported 4a
entry
catalyst
solventb
CH2Cl2
yieldc (%)
ee (%)
(6) Davies, H. M. L.; Hutchenson, D. K. Tetrahedron Lett. 1993, 34,
7243.
(7) Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001, 57, 1.
(8) (a) Davies, H. M. L.; Loe, Ø. Synthesis 2004, 2595. (b) Davies, H.
M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861.
(9) (a) Doyle, M. P.; Timmons, D. J.; Tumonis, J. S.; Gau, H.-M.;
Bloosey, E. C. Organometallics 2002, 21, 1747. (b) Doyle, M. P.; Eismont,
M. Y.; Bergbreiter, D. E.; Gray, H. N. J. Org. Chem. 1992, 57, 6103.
(10) (a) Davies, H. M. L.; Walji, A. M.; Nagashima, T. J. Am. Chem.
Soc. 2004, 126, 4271. (b) Davies, H. M. L.; Walji, A. M. Org. Lett. 2003,
5, 479. (c) Nagashima, T.; Davies, H. M. L. Org. Lett. 2002, 4, 1989.
(11) (a) Handbook of Fluorous Chsmistry; Gladysz, J. A., Curran, D.
P., Horvath, I. T., Eds.; Wiley-VCH: Weinheim, 2004. (b) Dobbs, A. P.;
Kimberley, M. R. J. Fluorine Chem. 2002, 118, 3. (c) de Wolf, E.; Van
Koten, G.; Deelman, B.-J. Chem. Soc. ReV. 1999, 28, 37. (d) Horvath, I. T.
Pure Appl. Chem. 1998, 31, 641.
1
2d
3e
4f
5
6
7d
8
4
4
4
4
4
82
87
80
86
39
53
47
66
79
81
65
77
73
48
49
51
56
47
47
54
60
62
72
74
61
85
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2/PFD
CH2Cl2
CH2Cl2
n-pentane
PFMC
PFMC
PFMC
CH2Cl2
n-pentane
BFP-4
BFP-4
BFP-4
9
4
4
4
10g
11h
12i
13i
Rh2(S-TBSP)4
Rh2(S-TBSP)4
(12) (a) Biffis, A.; Zecca, M.; Basato, M. Green Chem. 2003, 5, 170.
(b) Biffis, A.; Braga, M.; Basato, M. AdV. Synth. Catal. 2004, 5, 170.
(13) (a) Tzschucke, C. C.; Markert, C.; Glatz, H.; Bannwarth, W. Angew.
Chem., Int. Ed. 2002, 41, 4501. (b) Jenkins, P. M.; Steele, A. M.; Tsang,
S. C. Catal. Commun. 2003, 4, 45. (c) Ablan, C. D.; Hallet, J. P.; West, K.
N.; Jones, R. S.; Eckert, C. A.; Liotta, C. L.; Jessop, P. G. Chem. Commun.
2003, 2972. (d) Yamazaki, O.; Hao, X.; Yoshida, A.; Nishikido, J.
Tetrahedron Lett. 2003, 44, 8791.
a Reaction conditions: see text. b PFD ) perfluorodecalin; PFMC )
perfluoro(methylcyclohexane). c Isolated yield of the E product. d Diazo-
compound addition in 5 h. e Recycle of entry 1. f Recycle of entry 3.
g Recycle of entry 9. h Recycle of entry 10. i Literature data16 for the
reference catalyst tetrakis-dirhodium(II)-(S)-N-(tert-butylbenzensulfonyl)-
prolinate [Rh2(S-TBSP)4].
1842
Org. Lett., Vol. 7, No. 9, 2005

the literature,6,15,16 the E reaction product is formed in high
yields (diastereomeric ratio ) 98:2). Compared to the original
catalyst reported by Davies (entry 12), the perfluorinated
catalyst appears to be slightly more chemoselective but less
enantioselective (about 50% ee vs 60% favoring the same
(1R,2S)-product); we have tried to improve the reaction
outcome by adding the diazocompound very slowly to the
reaction mixture (entry 2) but observed no improvement in
selectivity. Nevertheless, the catalyst was found to be readily
recyclable upon extraction from the reaction mixture into a
fluorous solvent followed by solvent evaporation and redis-
solution into a fresh styrene solution in dichloromethane.
We have conducted an accurate screening of different
fluorous solvents in order to identify the best extractant for
our catalyst. Tests were performed by dividing into different
aliquots a sample of the reaction mixture after reaction and
then extracting each sample with a different fluorous solvent;
the concentration of Rh remaining in the reaction mixture
was subsequently evaluated by ICP-AAS (for experimental
details, see Supporting Information). The results reported in
Table 2 show that, although all fluorous solvents perform
phase appears to have a detrimental effect on the chemo-
selectivity but not on the enantioselectivity under the
employed reaction conditions. Apparently, such confinement
promotes side reactions of the transient carbenoid such as
dimerization to the corresponding alkene or reaction with
the diazocompound to the corresponding azine.
We have subsequently determined the effect of the reaction
solvent on the selectivity of the reaction. In fact, it is known
that use of hydrocarbon solvents such as n-pentane has a
positive effect on the enantioselectivity of chiral N-arylsul-
fonylprolinate catalysts (compare entries 12 and 13 in Table
1).6,15,16 Unfortunately, 4 is insoluble in n-pentane alone and
only slightly soluble in an n-pentane solution of styrene.
Therefore, we have tested two alternative protocols for
running the reaction in solvents of low polarity. First, we
tried to run the reaction in n-pentane using the catalyst in
BFP form (entry 8). We were pleased to see that the
enantioselectivity of the reaction indeed increased, although
to a lower extent than with the reference catalyst. The
reaction yield was also significantly higher than in the
reaction run with the BFP catalyst in dichloromethane;
however, it was still lower than in the homogeneous reaction.
Finally, we chose to try to run the reaction with the catalyst
dissolved in PFMC and no other organic solvent. Under these
conditions, the reaction product dissolves in the excess
styrene reagent, which builds up a separate phase and is
conveniently and quantitatively removed from the fluorous
phase containing the catalyst by simple decantation, without
the need for extraction with organic solvents. The catalyst
itself remains confined in the fluorous phase throughout the
reaction; only 2 ppm of rhodium, corresponding to 0.1%
metal leaching, is found in the product phase at the end of
the reaction. As it is reported in Table 1, entries 9-11, the
reaction yield under these conditions equals that of the
experiments in the homogeneous phase (entry 1), and the
enantioselectivity rises to 62% ee. The catalyst is fully
recyclable, with a slight decrease of the reaction yield
occurring only in the third reaction cycle; moreover, also
observed in this case is a significant increase in the
enantioselectivity upon recycling (up to 74% ee).
Table 2. Efficiency of the Extraction of 4 from
Cyclopropanation Reaction Mixtures into Different Fluorous
Solvents
fluorous solvent
% 4 extracted
perfluoro(methylcyclohexane)
perfluorodecalin
95
88
89
88
86
Fluorinert FC-77a
perfluoroheptane
Miteni RM101b
a Mixture of perfluoro(butyltetrahydrofurans). b Mixture of perfluoro-
(butyltetrahydrofurans) and perfluoro(propyltetrahydropyrans).
quite well, it is perfluoro(methylcyclohexane) (PFMC) that
gives the best results, enabling 95% catalyst recovery.
We have performed in this way two catalyst recycles
(Table 1, entries 3 and 4), observing no decrease in the
reaction yield and even a small improvement in the enan-
tioselectivity of the reaction.
We continued our study by investigating alternative
strategies for catalyst recovery and recycling. Running the
reaction under fluorous biphasic conditions results in a
dramatic drop of the chemoselectivity of the reaction,
whereas the enantioselectivity remains almost constant (entry
5). A less dramatic but still significant decrease in chemo-
selectivity is also observed using the catalyst in BFP form
(entry 6), and no improvement is seen on very slow addition
of the diazocompound (entry 7); the enantioselectivity is also
in this case fully comparable to that of the homogeneous
reaction. Thus, catalyst confinement in a separated fluorous
We have also performed a preliminary evaluation of the
catalytic performance of 4 in the asymmetric C-H bond
activation of cyclohexane. The results are reported in Table
3.
Our idea was to employ the reaction conditions reported
by Davies et al.17 (excess cyclohexane, 1 equiv of diazo-
compound, 0.01 equiv of catalyst, room temperature, con-
trolled diazocompound addition over 90 min), which imply
using cyclohexane as the reaction solvent. However, 4 turned
out to be only partially soluble in cyclohexane at room
temperature. Nevertheless, the recorded yield of C-H
insertion product is quite good, although the achieved ee is
significantly lower than that of the reference catalyst
(compare entries 1 and 6, Table 3). We have tried to improve
the reaction ee by decreasing the reaction temperature;17
however, this further decreases the solubility of the perflu-
(14) Curran, D. P.; Hadida, S.; Mu, H. J. Org. Chem. 1997, 62, 6714.
(15) (a) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall,
M. J. J. Am. Chem. Soc. 1996, 118, 6897. (b) Davies, H. M. L.; Panaro, S.
P. Tetrahedron 2000, 56, 4871.
(16) Doyle, M. P.; Zhou, Q.-L.; Charnsangavej, C.; Longoria, M. A.;
McKervey, M. A.; Garcia, C. F. Tetrahedron Lett. 1996, 37, 4129.
(17) Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc.
2000, 122, 3063.
Org. Lett., Vol. 7, No. 9, 2005
1843

able to give the C-H insertion product. Indeed, the main
decomposition byproduct, which in this case has been
identified as the azine, partly precipitates out of the liquid-
liquid biphasic system in the course of the reaction. We have
also evaluated the performance of the BFP-supported catalyst
(entries 4 and 5). The reaction yield is again somewhat lower
than in the homogeneous phase experiment, but the ee
remains almost the same. The catalyst can be easily separated
from the reaction mixture by simple filtration; leaching of
Rh in the organic phase amounts to 3.5% of the total metal
present. Catalyst recycling is possible; however, the reaction
yield in the second cycle decreases considerably (entry 5),
whereas only a small decrease in enantioselectivity is
observed.
Table 3. Asymmetric C-H Bond Activation with
Homogeneous and Supported 4a
entry
catalyst
T (°C)
yieldb (%)
ee (%)
1
2
3
4
5d
6e
4
4
4c
25
10
25
25
25
25
71
22
56
59
33
74
61
61
61
58
53
92
BFP-4
BFP-4
Rh2(S-DOSP)4
In conclusion, we have developed a fluorous chiral
dirhodium(II) catalyst that displays excellent chemo- and
regioselectivity and good enantioselectivity in cyclopro-
panation reactions. The catalyst can be simply and thoroughly
separated from the reaction mixture and is recyclable.
Furthermore, it enables the use of a reaction protocol without
organic solvents besides the reagents and a tiny amount of
fluorous solvent. Finally, the catalyst is also active and
selective in C-H bond activation reactions, although in this
case the solubility of the catalyst in the reaction environment
and/or its recyclability need to be improved. We are currently
working toward such improvements and also at further
improving the enantioselectivity of the catalyst.
a Reaction conditions: see text. b Isolated yield. c Catalyst dissolved in
PFMC. d Recycle of entry 4. e Literature data17 for the reference catalyst
tetrakis-dirhodium(II)-(S)-N-(n-dodecylbenzensulfonyl)-prolinate [Rh2(S-
DOSP)4].
orinated catalyst to such an extent that the reaction yield
drops considerably (entry 2). The catalyst can be also in this
case quantitatively separated from the reaction mixture by
extraction into PFMC. In fact, although many hydrocarbons
are miscible with PFMC at room temperature,11a,18 we have
found that cyclohexane/PFMC mixtures remain biphasic up
to 53 °C.
We have tried to get rid of the solubility problems by
running the reaction with the catalyst in a separated fluorous
phase. Use of a liquid-liquid biphasic system with the
catalyst dissolved in PFMC allows, as in the previous case,
an easy and quantitative separation of the catalyst from the
reaction mixture. The enantioselectivity is fully comparable
to that obtained in the homogeneous phase (entry 3);
however, the chemoselectivity of the reaction is lower, since
the carbenoid intermediate tends to react further before being
Acknowledgment. Financial support from the University
of Padova “Progetti di Ateneo 2002” is gratefully acknowl-
edged. We wish to thank Miteni SpA for a generous gift of
perfluorinated chemicals and Dr. Giulia Zanmarchi, Univer-
sity of Padova, for the ICP-AAS measurements.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) Barthel-Rosa, L. P.; Gladysz, J. A. Coord. Chem. ReV. 1999, 190,
0-192, 587.
OL050486U
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Org. Lett., Vol. 7, No. 9, 2005