Asymmetric intermolecular C-H activation, using immobilized dirhodium tetrakis((S)-N-(dodecylbenzenesulfonyl)-prolinate) as a recoverable catalyst

Article abstract of DOI:10.1021/ol0273506

(Matrix presented) Heterogenization of dirhodium tetrakis((S)-N-dodecylbenzenesulfonyl)prolinate) (Rh₂(S-DOSP) ₄) can be readily achieved on a pyridine functionalized highly cross-linked polystyrene resin. The immobilized complex is readily recycled and exhibits excellent catalytic activity for asymmetric intermolecular C-H activation by means of rhodium carbenoid induced C-H insertion.

Full text of DOI:10.1021/ol0273506

ORGANIC
LETTERS
2003
Vol. 5, No. 4
479-482
Asymmetric Intermolecular C−H
Activation, Using Immobilized Dirhodium
Tetrakis((S)-N-(dodecylbenzenesulfonyl)-
prolinate) as a Recoverable Catalyst
Huw M. L. Davies* and Abbas M. Walji
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York,
Buffalo, New York 14260-3000
hdaVies@acsu.buffalo.edu
Received November 25, 2002
ABSTRACT
Heterogenization of dirhodium tetrakis((S)-N-dodecylbenzenesulfonyl)prolinate) (Rh2(S-DOSP)4) can be readily achieved on a pyridine functionalized
highly cross-linked polystyrene resin. The immobilized complex is readily recycled and exhibits excellent catalytic activity for asymmetric
intermolecular C−H activation by means of rhodium carbenoid induced C−H insertion.
Immobilization of chiral catalysts for asymmetric carbenoid
transformations has attracted the interest of many research
groups.1 Several copper, ruthenium, and rhodium(II) com-
plexes have been immobilized onto organic and inorganic
supports and used as recoverable catalysts.1 Asymmetric
cyclopropanation2 has been the standard reaction to evaluate
these catalysts, with the exception of one study of asymmetric
intramolecular C-H activation with dirhodium tetracarboxami-
dates.1b We have recently discovered a very general method
for asymmetric intermolecular C-H activation by means of
rhodium-carbenoid induced C-H insertion.3-5 A requirement
for a successful outcome in these C-H activations is the
use of carbenoids containing both donor and acceptor
groups.3,4 As the method allows rapid access to a range of
pharmaceutically relevant chiral building blocks, the avail-
ability of an effective immobilized chiral catalyst for this
chemistry would broaden its utility for diversity synthesis.
Herein we report the heterogenization of dirhodium tetrakis-
(1) (a) Bergbreiter, D. E.; Chen, B.; Morvant, M. Tetrahedron Lett. 1991,
32, 2731. (b) Doyle, M. P.; Eismont, M. Y.; Bergbreiter, D. E.; Gray, H.
N. J. Org. Chem. 1992, 57, 6103. (c) Burguette, M. I.; Fraile, J. M.; Garcia,
J. I.; Garcia-Verdugo, E.; Luis, S. V.; Mayoral, J. A. Org. Lett. 2000, 2,
3905. (d) Burguette, M. I.; Fraile, J. M.; Garcia, J. I.; Garcia-Verdugo, E.;
Luis, S. V.; Mayoral, J. A. J. Org. Chem. 2001, 66, 8893. (e) Diaz-Requejo,
M. M.; Belderrain, T. R.; Nicasio, M. C.; Perez, P. J. Organometallics 2000,
19, 285. (f) Glos, M.; Reiser, O. Org. Lett. 2000, 2, 2045. (g) Annunziata,
R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Pitillo, M. J. Org. Chem. 2001,
113, 2587. (h) Nagashima, T.; Davies, H. M. L. Org. Lett. 2002, 4, 1989.
(i) Doyle, M. P.; Timmons, D. J.; Tumonis, S. J.; Gau, H.; Blossey, C. E.
Organometallics 2002, 21, 1747. (j) Cornejo, A.; Fraile, J. M.; Garcia, J.
I.; Garcia-Verdugo, E.; Gil, M. J.; Legarreta, G.; Luis, V. S.; Martinez-
Merino, V.; Mayoral, J. A. Org Lett. 2002, 4, 3927. For reviews see: (k)
Rechavi, D.; Lemaire, M. Chem. ReV. 2002, 102, 3467. (l) Bergbreiter, D.
E. In Chiral Catalyst Immobilization and Recycling; De Vos, D. E.,
Vankelecom, I. F. J., Jacobs, P. A., Eds.; Wiley-VCH: Wienheim, Germany,
2000; p 43.
(3) For reviews, see: (a) Davies, H. M. L. J. Mol. Catal. A: Chem.
2002, 189, 125. (b) Davies, H. M. L.; Antoulinakis, E. G. J. Organomet.
Chem. 2001, 617-618, 47.
(4) (a) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075.
(b) Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999, 1, 233.
(c) Davies, H. M. L.; Antoulinakis, E. G.; Hansen, T. Org. Lett. 1999, 1,
383. (d) Davies, H. M. L.; Hansen, T.; Hopper, D.; Panaro, S. J. Am. Chem.
Soc. 1999, 121, 6509. (e) Davies, H. M. L.; Hansen, T.; Churchill, M. R.
J. Am. Chem. Soc. 2000, 122, 3063. (f) Davies, H. M. L.; Stafford, D. G.;
Hansen, T.; Churchill, M. R.; Keil, K. M. Tetrahedron Lett. 2000, 41, 2035.
(g) Davies, H. M. L.; Antoulinakis, E. G. Org. Lett. 2000, 2, 3153. (h)
Davies, H. M. L.; Ren, P. J. Am. Chem. Soc. 2001, 123, 2070. (i) Davies,
H. M. L.; Ren, P.; Jin, Q. Org. Lett. 2001, 3, 3587. (j) Davies, H. M. L.;
Gregg, T. Tetrahedron Lett. 2002, 43, 4951. (k) Davies, H. M. L.; Walji,
A. M.; Townsend, R. J. Tetrahedron Lett. 2002, 43, 4981.
(5) For studies by other groups on asymmetric intermolecular C-H
activation by carbenoids, see: (a) Axten, J. M.; Ivy, R.; Krim, L.; Winkler,
J. D. J. Am. Chem. Soc. 1999, 121, 6511. (b) Mu¨ller, P.; Tohill, S.
Tetrahedron 2000, 56, 1725.
(2) Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001, 59, 1-302.
10.1021/ol0273506 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/17/2003

((S)-N-dodecylbenzenesulfonyl)prolinate) Rh2(S-DOSP)4 1a
and its use as a highly efficient catalyst for asymmetric
intermolecular C-H activation.
on the rate of the reaction would be consistent. Changes in
the color of the solution after diazo addition and cessation
of nitrogen gas evolution were used to determine the end-
point of the reaction. After filtration of the reaction mixture,
the resin was washed with toluene (three times) and dried
before reuse in the next cycle.
Ten cycles of C-H activation with 3-Rh2(S-DOSP)4 were
readily achieved and the products could be obtained in high
purity by evaporation of the solvent and excess diene,
followed by filtration. Good product yields (84-79%) and
a slight drop in enantiomeric excess (ee) from 88% to 84%
was observed over the 10 cycles (Table 1). The slight drop
Table 1. Asymmetric Intermolecular C-H Activation of
1,4-Cyclohexadiene with Immobilized Rh2(S-DOSP)4
The highly crossed-linked polystyrene (Argopore)6 resin
with benzyloxymethyl-pyridine linker 37 has been shown to
be a remarkable system for immobilization of complexes Rh2-
(S-TBSP)4 1b and Rh2(S-biTISP)2 2.1h These immobilized
catalysts are very effective for intermolecular cyclopropa-
nations by donor/acceptor carbenoids.1h This led us to explore
the similar heterogenization of Rh2(S-DOSP)4 1a, which is
the most generally effective catalyst for intermolecular C-H
activation.3,4 Agitating a mixture of the resin and Rh2(S-
DOSP)4 in toluene for 2 h gave, after filtration and washing,
purple beads of 3-Rh2(S-DOSP)4, indicating metal coordina-
tion to the pyridine. ICP analysis of the resin beads gave a
measurement corresponding to 0.17 mmol/g catalyst loading
(Scheme 1).
cycle
time, min
yield, %a
ee, %
1
3
5
8
10
20
20
23
25
30
79 (81)
81 (81)
80 (83)
82
88
87
87
84
84
84
a Yields in parenthesis determined by NMR with DMAP as internal
standard.
in enantioselectivity on recycling the catalyst is far less than
had been previously reported for cyclopropanations induced
by immobilized Rh2(S-TBSP)4.1h
The activity of the catalyst was further tested by using
recycled catalyst for a series of C-H insertions with several
different aryldiazoacetates (Table 2). A final cycle with
methyl phenyldiazoacetate (4) was used to confirm that the
yields and ee values are comparable to those obtained with
fresh catalyst. No cross contamination between successive
cycles was observed from the 1H NMR spectra of the crude
reaction mixtures.
Scheme 1
The C-H activation of 1,3- or 1,4-cyclohexadiene with
the donor/acceptor carbenoids is useful for the synthesis of
a number of pharmaceutical agents. Previously, we have
utilized these reactions in the asymmetric syntheses of (+)-
indatraline,4j (+)-cetiedil,4k and (+)-sertraline (Zoloft).4b The
immobilized catalyst 3-Rh2(S-DOSP)4 is also very effective
at the asymmetric synthesis of these pharmaceutical agents,
as the catalyst is able to furnish the key intermediates in
high ee and purity (Scheme 2).
The C-H activation with the donor/acceptor carbenoids
is a strategic reaction that can be considered as a surrogate
of some of the classic organic synthesis reactions, such as
the Michael reaction,4h the aldol reaction,4c,g the Mannich
reaction,4d and the Claisen rearrangment.4i A series of
reactions was explored to determine if the immobilized
catalyst 3-Rh2(S-DOSP)4 was effective in the full range of
these surrogate reactions.
To evaluate the catalytic activity of 3-Rh2(S-DOSP)4 C-H
activation of 1,4-cyclohexadiene was used as the standard
reaction.4f With use of 0.5 mol % of 3-Rh2(S-DOSP)4 in
toluene and 5 equiv of 1,4-cyclohexadiene, dropwise addition
of methyl phenyldiazoacetate 4 resulted in efficient inter-
molecular C-H activation. Even though the polymer support
consists of polystyrene, it does not appear to interfere with
the C-H activation process. The rate of agitation was
electronically controlled and held constant, so any effects
(6) Purchased from Argonaut Technologies (www.argotech.com).
(7) Derivatized from Argopore-Wang resin (hydroxyl loading 0.65 mmol/
g).
480
Org. Lett., Vol. 5, No. 4, 2003

catalyst4i was similarly seen in the reaction catalyzed by
3-Rh2(S-DOSP)4.
Table 2. Asymmetric C-H Activation of 1,4-cyclohexadiene
with Various Aryl- and 3-Thienyldiazoacetates and Recycled
Catalyst
Scheme 3
The Michael reaction surrogate involved C-H activation
of silyl enol ethers such as triisopropylsiloxycyclohexene
(10).4h 3-Rh2(S-DOSP)4-catalyzed decomposition of 4 in the
presence of 10 gave the C-H activation product as a mixture
Scheme 4
An example of the Claisen rearrangement surrogate is the
reaction of 1-(diphenyl-tert-butylsilyl)hexene (8) shown in
Scheme 3.4i 3-Rh2(S-DOSP)4-catalyzed decomposition of 4
in the presence of 8 gave the C-H activation product 9 in
87% de and 94% ee. The high enantio-, diastereo-, and
regioselectivity that has been observed with the homogeneous
of diastereomers (63:37 dr) in 60% yield, where the major
diastereomer 11 was formed in 89% ee (Scheme 4). The
Scheme 2
Org. Lett., Vol. 5, No. 4, 2003
481

preferential occurrence of C-H activation instead of cyclo-
propanation of the electron-rich double bond parallels the
results obtained in the homogeneous reaction4h and is due
to the demanding steric requirements of the donor/acceptor
rhodium carbenoids.3
C-H activation R to O-silyl groups generates silyl-
protected â-hydroxy esters and can be considered as a
surrogate of the aldol reaction.4g,c The 3-Rh2(S-DOSP)4-
catalyzed reaction of 4 with tetraethoxysilane (12) as the
substrate generates the syn product 13 in >90% de, 96% ee,
and 72% yield (Scheme 5). Similarly, the 3-Rh2(S-DOSP)4-
DOSP)4-catalyzed reaction of 4 with N-BOC-pyrrolidine
(16), which demonstrates the high diastereoselectivity and
enantioselectivity that is possible with this chemistry. Three
cycles were conducted without notable effect on the outcome
of the reaction, as the C-H insertion product 17 was formed
in 90% de, 88-86% ee, and 70-67% yield (Table 4). The
Table 4. Asymmetric C-H Activation as a Surrogate of the
Mannich Reaction with Recycled Catalyst
Scheme 5
cycle
de, %
ee, %
yield, %
1
2
3
90
90
90
88
88
86
70
67
68
stereoselectivity exhibited with 3-Rh2(S-DOSP)4 is compa-
rable to that obtained in the homogeneous reaction.4d
The immobilization of Rh2(S-DOSP)4 has led to a highly
efficient re-usable catalyst for asymmetric intermolecular
C-H activation. The present study extends the applicability
of asymmetric carbenoid transformations for diversity syn-
thesis. In general the regio-, diastereo-, and enantioselectivity
of these C-H activation processes are retained when using
an immobilized catalyst instead of a homogeneous catalyst.
A complete study directed toward understanding the various
aspects of this catalyst immobilization is underway.
catalyzed reaction of 4 with TBS-protected crotyl alcohol
(14) was very effective. The syn product 15 was formed in
82% ee, >94% de, and 70% yield (Table 3). Repeating the
Table 3. Asymmetric C-H Activation as a Surrogate of the
Aldol Reaction with Recycled Catalyst
Acknowledgment. Financial support of this work by the
National Science Foundation (CHE-0092490) and the Na-
tional Institutes of Health (DA06301 and DA15225) is
gratefully acknowledged. Initial studies by Dr. Tadamichi
Nagashima are gratefully acknowledged.
cycle
de, %
ee, %
yield, %
1
2
3
>94
>94
>94
82
82
82
70
68
68
Supporting Information Available: Experimental data
for the synthesis of Rh2(S-DOSP)4 on solid support and for
the asymmetric C-H activation. This material is available
free of charge via the Internet at http://pubs.acs.org.
reaction with recycled catalyst gave virtually identical results.
The very high diastereoselectivity observed in these reactions
matches the results obtained with homogeneous catalysis.4g,c
The C-H activation R to nitrogen is the Mannich reaction
surrogate. An example of this reaction is the 3-Rh2(S-
OL0273506
482
Org. Lett., Vol. 5, No. 4, 2003