Recognition and catalysis in allylic alkylations.

Article abstract of DOI:10.1021/ol0258637

[structure: see text] A cavitand outfitted with a chelated palladium atom catalyzes allylic alkylation reactions. Molecular recognition by the cavitand distinguishes between closely related structures and results in subtle substrate specificities.

Full text of DOI:10.1021/ol0258637

ORGANIC
LETTERS
2002
Vol. 4, No. 11
1887-1890
Recognition and Catalysis in Allylic
Alkylations
Christoph Gibson and Julius Rebek, Jr.*
The Skaggs Institute for Chemical Biology and The Department of Chemistry,
The Scripps Research Institute, MB-26, 10550 North Torrey Pines Rd.,
La Jolla, California 92037
jrebek@scripps.edu
Received March 12, 2002
ABSTRACT
A cavitand outfitted with a chelated palladium atom catalyzes allylic alkylation reactions. Molecular recognition by the cavitand distinguishes
between closely related structures and results in subtle substrate specificities.
One goal of modern physical organic chemistry is to merge
molecular recognition with chemical catalysis. To that end,
synthetic receptors have been furnished with appropriate
functional groups,1 with the idea of placing the functionality
of the host near the resident guest. Placing functional groups
on concave surfaces is challenging, but progress has been
made with inwardly directed carboxyl groups2 and porphyrin-
containing macrocycles.3 These show high affinities for
complementary guests4 and accelerate reactions not catalyzed
by enzymes.5 The synthesis and evaluation of a cavitand
bearing a palladium catalyst near the guest site is reported
here. The system expresses molecular recognition in its
catalytic action.
(Figure 1).6 Palladium-catalyzed reactions of monosubstituted
allylic substrates such as 1 or 2 with nucleophiles typically
result in linear products (3).7 In contrast, aryl-substituted allyl
acetates (R ) Ar) yield predominantly the branched isomer
-
4 (Nu- ) HC(CO2Me)2 ) with good regio- and enantio-
selectivities when compound 5 is employed as the palladium
ligand.
Catalyst precursor exo-7 features a diphenyl-substituted
oxazoline attached to a cavitand. Such cavitands are capable
of binding size- and shape-complementary molecules such
as adamantanes.8 The geminal phenyl groups of the oxazoline
were expected to destabilize η3-complex B as well as the
transition states leading to this isomer (Figure 2). The
pathway involving the η3-complex A should dominate, as
the residue R of the substrate is forced into the cavitand.
Nucleophilic attack takes place preferentially at the allyl
terminus trans to the Pd-P bond in such complexes,9 and
reaction at the unsubstituted allyl end should be favored.
The specific arrangement draws on the work of Pfaltz et
al., who recently described the chiral palladium ligand 5
(1) For recent reviews, see: (a) Murakami, Y.; Kikuchi, J.; Hisaeda, Y.;
Hayashida, O. Chem. ReV. 1996, 96, 721. (b) Motherwell, W. B.; Bingham,
M. J.; Six, Y. Tetrahedron 2001, 57, 4663.
(2) Renslo, A. R.; Rebek, J., Jr. Angew. Chem., Int. Ed. 2000, 40, 1221.
(3) Anderson, S.; Anderson, H. L.; Sanders, J. K. M. J. Chem. Soc.,
Perkin Trans. 1 1995, 2247.
(4) Wash, P. L.; Renslo, A. R.; Rebek, J., Jr. Angew. Chem., Int. Ed.
2001, 39, 3281.
(5) Marty, M.; Clyde-Watson, Z.; Twyman, L. J.; Nakash, M.; Sanders,
J. K. M. Chem. Commun. 1998, 20, 2265.
(6) Pre´toˆt, R.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1998, 37, 323.
(7) (a) A° kermark, B.; Zetterberg, K.; Hansson, S.; Krankenberger, B.;
Vitagliano, A. J. Organomet. Chem. 1987, 335, 133. (b) Sjo¨grin, M. P. T.;
Hansson, S.; A° kermark, B.; Vitagliano, A. Organometallics 1994, 13, 1963.
(8) Rudkevich, D. M.; Hilmersson, G.; Rebek, J., Jr. J. Am. Chem. Soc.
1998, 120, 12216.
10.1021/ol0258637 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/09/2002

Figure 2. Predicted nucleophilic attack on the η3-copmlexes A
and B. The steric hindrance caused by the geminal phenyl groups
of the oxazoline favors a reaction pathway involving η3-complex
A that results in the formation of the linear product 3.
Figure 1. Palladium-catalyzed allylic alkylation. The design of
supramolecular palladium ligand exo-7 based on ligand 5. Ligand
6 was used for control experiments.
Contrary to ligand 6, the reaction rate varies significantly
with different substrates when exo-7 is employed as the
palladium ligand. The conversion of substrates 2b and 2c
was complete after 2 days, whereas the reaction of the bulkier
substrates 2d and 2e were approximately four times slower.
Remarkably, the smaller substrate 2a exhibited the lowest
reaction rate.
The synthesis of ligand exo-7 is shown in Scheme 1. First,
chlorophosphite 10 was generated in situ by treating diol
910 with PCl3 using pyridine as the base. The reaction of 10
with alcohol 11 in the presence of triethylamine yielded a
7:3 mixture of exo-7 and endo-7, which could be separated
by chromatography.11 The presence of Et3N proved essential
for the selective formation of exo-7 and implies that Et3-
NHCl occupies the interior of intermediate 1012 and the
formation of the undesired isomer endo-7 is suppressed. Both
phosphites are configurationally stable up to 100 °C; at higher
temperatures they decompose.
Competiton experiments interrogated the substrate speci-
ficity of exo-7 (Table 2). The η3-complexes of exo-7 and 6
bear a single positive charge and are suited for study by
electrospray mass spectrometry. The structural differences
of the η3-complexes are minor, so the relative abundances
of their signals in the mass spectra were assumed to
accurately reflect the solution concentrations of the allyl
palladium species present in the reaction mixture. Surpris-
ingly, after one turnover, the mass spectrum of a 1:1 mixture
of substrates 2a and 2b in the presence of exo-7 revealed a
91:9 distribution in favor of the 2a-derived η3-complex. After
4 days, the mixture of 2a and 2b yielded predominantly
product 3a, although substrate 2b showed an overall reaction
rate substantially higher than that of 2a (compare Table 1).
These data suggest that palladium(0) species 8 forms the η3-
complex more quickly with substrate 2a, but this complex
is practically inert to nucleophilic attack by the malonate.
Substrate 2a is an inhibitor of catalyst 8. Model ligand 6
showed the same preference for substrate 2a without inhibi-
tory effects. Substrate 2b also adds more rapidly to the
The reactions of substrates 2a-e with dimethyl malonate
were tested with cavitand exo-7 and ligand 6 (Table 1). In
all cases, the linear products 3a-e were exclusively formed.
(9) (a) Sprinz, J.; Kiefer, M.; Helmchen, G.; Reggelin, M.; Huttner, G.;
Walter, O.; Zsolnai, L. Tetrahedron Lett. 1994, 35, 1523. (b) Brown, J.
M.; Hulmes, D. J.; Guiry, P. J. Tetrahedron 1994, 50, 4493. (c) Togni, A.;
Burckhardt, U.; Gramlich, V.; Pregosin, P. S.; Salzmann, R. J. Am. Chem.
Soc. 1996, 118, 1031.
(10) Renslo, A. R.; Rudkevich, D. M.; Rebek, J., Jr. J. Am. Chem. Soc.
1999, 121, 7459.
(11) The structural assignment is mainly based on the capability of
1
binding guest molecules, which was determined by means of H NMR in
C6D5CD3. Cavitand exo-7 showed with an association constant Kass of
approximately 100 M-1 a distinct affinity to N-adamant-1-yl-3-p-tolyl-
acrylamide. In the case of endo-7, however, no encapsulation could be
detected, which indicates that the cavity of this stereoisomer is blocked by
the introversive oxazoline.
(12) Ma, S.; Rudkevich, D. M.; Rebek, J., Jr. Angew. Chem., Int. Ed.
1999, 38, 2600.
1888
Org. Lett., Vol. 4, No. 11, 2002

Scheme 1
Table 1. Allylic Alkylation of Various Substrates 2a-e Using
Ligands exo-7 or 6a
a Using 1.4 mol % [Pd(C3H5)Cl]2, 3.2 mol % L, 3 equiv of CH2(CO2Me)2
and N,O-bis(trimethylsilyl)acetamide (BSA). b Substrate was not completely
converted.
palladium(0) species than the allyl acetate 2c. The rate of
the oxidative addition depends on the connectivity of the
homoallylic carbon atom; it decreases in the order 2a
(secondary) > 2b (tertiary) > 2c (quaternary).
To address this connectivity effect, we examined substrates
2b, 2d, and 2e, all of which represent a tertiary carbon atom
in the homoallylic position (Table 2 and Figure 3). Pairwise
comparison of these substrates with palladium ligand 6
showed no significant difference in reaction rates for either
the oxidative addition or the overall reaction. Competition
experiments of 2b and 2d with exo-7 showed, after ap-
Figure 3. Mass spectrometric analysis of reaction mixtures containing an equimolar amount of two substrates after one turnover using
palladium ligands exo-7 (upper row) or 6 (lower row).
Org. Lett., Vol. 4, No. 11, 2002
1889

Table 2. Allylic Alkylation of Various Substrates 2a-e Using Ligands exo-7 or 6a
ligand exo-7 (L)
ligand 6 (L)
ratio of
η3-complexesb
yieldc
(time)
product
distributiond
ratio of
η3-complexese
yield
product
distributiond
substrates
(time)
2a and 2b
2b and 2c
2b and 2d
2b and 2e
2d and 2e
2a :2b 91:9
2b:2c 95:5
2b:2d 32:68
2b:2e 70:30
2d :2e 87:13
20% (4 d)
35% (2 d)
32% (2 d)
35% (2 d)
29% (2 d)
3a :3b 85:15
3b:3c 91:9
3b:3d 29:71
3b:3e 67:33
3d :3e 86:14
2a :2b 96:4
2b:2c 99:1
2b:2d 48:52
2b:2e 49:51
2d :2e 50:50
36% (80 min)
61% (80 min)
46% (80 min)
58% (80 min)
64% (80 min)
3a :3b 87:13
3b:3c 98:2
3b:3d 42:58
3b:3e 52:48
3d :3e 47:53
a For experimental conditions, see Table 1. b Determined by mass spectrometry after 2 h. c Calculated by halving the sum of the individual yields of both
1
products. d Determined by H NMR after workup. e Determined by mass spectrometry after 20 min.
proximately one turnover, a 32:68 distribution in favor of
the substrate 2d-derived η3-complex. The mass spectrum of
substrates 2b and 2e showed nearly the same ratio, but the
allyl acetate 2b was favored. The mass spectrum of a mixture
of 2d and 2e revealed a considerable substrate specificity of
87:13 in favor of 2d. The ability of catalyst 8 to stabilize
the transition state of the oxidative addition decreases in the
order cyclohexyl (2d) > iso-propyl (2b) > 1-ethyl pentyl
(2e). The selectivity in product formation of 3b, 3d, and 3e
correlates strongly with the substrate specificity, associated
with the oxidative addition. This result underscores the
potential of cavitand-containing catalysts in organic synthesis.
In summary, the palladium complex of a cavitand receptor
catalyzes allylic alkylations and exhibits a subtle substrate
specificity that distinguishes between closely related struc-
tures. These properties encourage further development of
cavitands as regio- and enantioselective catalysts.
Acknowledgment. We are grateful for financial support
from the Skaggs Research Foundation, the National Institutes
of Health, and the Humboldt Foundation.
Supporting Information Available: Representative ex-
perimental procedures and selected spectral characterization
for the compounds reported herein. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0258637
1890
Org. Lett., Vol. 4, No. 11, 2002