Electron-poor benzonitriles as labile, stabilizing ligands in asymmetric catalysis.

Article abstract of DOI:10.1021/ol017218q

[structure: see text] A chiral palladium catalyst [(S)-MeObiphep)Pd(NCAr)2(SbF6)2, (S)-4c], has been developed for a variety of asymmetric transformations. (S)-4c is bench-stable and has activity comparable to that of the nitrile free Lewis acid catalyst

Full text of DOI:10.1021/ol017218q

ORGANIC
LETTERS
2002
Vol. 4, No. 5
727-730
Electron-Poor Benzonitriles as Labile,
Stabilizing Ligands in Asymmetric
Catalysis
Jennifer J. Becker, Lori J. Van Orden, Peter S. White, and Michel R. Gagne´*
Department of Chemistry CB #3290, UniVersity of North Carolina,
Chapel Hill, North Carolina 27599-3290
mgagne@unc.edu
Received December 12, 2001
ABSTRACT
A chiral palladium catalyst [(S)-MeObiphep)Pd(NCAr)2(SbF6)2, (S)-4c], has been developed for a variety of asymmetric transformations. (S)-4c
is bench-stable and has activity comparable to that of the nitrile free Lewis acid catalyst for Diels−Alder, hetero-Diels−Alder, and glyoxylate-
ene reactions.
Dicationic platinum(II) and palladium(II) complexes are well-
known Lewis acid catalysts for a variety of asymmetric
transformations;1 however, the free dications tend to be
extremely hygroscopic and often form a µ-OH dimer upon
exposure to water.2 In the case of platinum dications, these
Lewis acids are often sufficiently electrophilic to also abstract
chloride from halogenated solvents such as dichloromethane.
As a result, we and others have typically generated the active
catalyst in situ by AgX or HX treatment of suitable
precursors. To increase the stability and/or isolability of these
dicationic catalysts, acetonitrile or benzonitrile ligands have
been added to bind the open coordination sites, which results
in a bench-stable catalyst that requires no further activation.3
Although we have found no direct comparisons between
catalysts with and without nitrile ligands, we postulated that
these nitrile ligands, while stabilizing the dication, were also
acting as competitive inhibitors for substrates and compro-
mising the potential activity of the catalysts. To obtain
catalyst precursors that were more reactive than the CH3-
CN- or PhCN-stabilized dications but still maintained the
desirable properties of air/water stability, we chose to
investigate the effect of benzonitrile ligands with electron
withdrawing groups on Lewis acid catalysis.
We began by investigating the Diels-Alder reaction in
eq 1. The Lewis acid catalysts were generated in situ by
(1) (a) Becker, J. J.; White, P. S.; Gagne´, M. R. J. Am. Chem. Soc. 2001,
122, 9478-9479. (b) Ghosh, A. K.; Matsuda, H. Org. Lett. 1999, 1, 2157-
2159. (c) Koh, J. H.; Larsen, A. O.; Gagne´, M. R. Org. Lett. 2001, 3, 1233-
1236. (d) Pignat, K.; Vallotto, J.; Pinna, F.; Strukul, G. Organometallics
2000, 19, 5160-5167. (e) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T.
J. Am. Chem. Soc. 1998, 120, 4548-4549. (f) Hori, K.; Kodama, H.; Ohta,
T.; Furukawa, I. Tetrahedron Lett. 1996, 37, 5947-5950.
(2) For example, see: (a) Gavagnin, R.; Cataldo, M.; Pinna, F.; Strukul,
G. Organometallics 1998, 17, 661-667. (b) Bandini, A. L.; Banditelli, G.;
Demartin, F.; Manassero, M.; Minghetti, G. Gazz. Chim. Ital. 1993, 123,
417-423. (c) Longato, B.; Pilloni, G.; Valle, G.; Corain, B. Inorg. Chem.
1988, 27, 956-958. (d) Bushnell, G. W.; Dixon, K. R.; Hunter, R. G.;
McFarland, J. J. Can. J. Chem. 1972, 50, 3694-3699.
addition of 2.5 equiv of AgSbF6 and 2.0 equiv of various
(3) (a) Hao, J.; Hatano, M.; Mikami, K. Org. Lett. 2000, 2, 4059-4062.
(b) Oi, S.; Terada, E.; Ohuchi, K.; Kato, T.; Tachibana, Y.; Inoue, T. J.
Org. Chem. 1999, 64, 8660-8662. (c) Hori, K.; Kodana, H.; Ohta, T.;
Furukawa, I. J. Org. Chem. 1999, 64, 5017-5023. (d) Oi, S.; Kashiwwagi,
K.; Inoue, Y. Tetrahedron Lett. 1998, 39, 6253-6256. (e) Oi, S.; Kashiwagi,
K.; Terada, E.; Ohuchi, K.; Inoue, Y. Tetrahedron Lett. 1996, 37, 6351-
6354. (f) Hori, K.; Ito, J.; Ohta, T.; Furukawa, I. Tetrahedron 1998, 54,
12737-12744.
10.1021/ol017218q CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/02/2002

nitriles to ((S)-MeObiphep)PdCl2 in dichloromethane (Scheme
1). After 30 min of stirring at ambient temperature, the
caused it to be prematurely removed at the point the AgCl
was filtered away. Nevertheless, the rate data clearly
established a kinetic inhibitory role for the stabilizing nitrile
ligand.
On the basis of solubility and reactivity considerations,
we chose to isolate the Lewis acid catalyst (S)-4c (Scheme
2). Treating ((S)-MeObiphep)PdCl2 with 2.5 equiv of AgSbF6
Scheme 1. In Situ Generated Catalysts
Scheme 2. Synthesis of Bench-Stable Lewis Acid Catalysts
solutions were filtered from the silver salts under N2
atmosphere and dienophile was added. After the mixture was
cooled to -78 °C, 15 equiv of cyclopentadiene (CpH) was
added, and the reactions periodically monitored by GC.4
Consistent with our original hypothesis, the rate of
conversion to Diels-Alder product was dependent on the
added nitrile,5 with the most active catalyst being generated
with the least coordinating pentafluorobenzonitrile ligand
(99% conv, 8 h, Figure 1). The catalyst generated in the
under N2 generated the bright orange dication, which quickly
turned yellow upon addition of 10 equiv of 3,5-bis(trifluo-
romethyl)benzonitrile. After stirring for 1 h, the reaction
mixture was opened to the atmosphere, and the silver salts
were filtered. The yellow solid was washed with hexanes to
remove excess nitrile, and (S)-4c was isolated in 82% yield.
To directly compare the activity of (S)-4c with a more
common stabilizing ligand, 4a was also synthesized.6 Both
(S)-4c and 4a are air- and water-stable for months and are
routinely stored on the benchtop.7
An X-ray structure of (R)-4c was obtained (Figure 2) by
Figure 1. Conversion to Diels-Alder product vs time for eq 1.
presence of benzonitrile was considerably less active with
only 66% conversion after 8 h. Surprisingly, on the basis of
the trends in the data, the catalyst generated from 3,5-bis-
(trifluoromethyl)benzonitrile 3c was the least reactive of
those tested (54% conv), a phenomenon that was ultimately
traced to the catalyst/nitrile adduct’s lower solubility, which
Figure 2. CHEM-3D representation of the P2Pd2+ fragment of (R)-
4c, obtained from the X-ray structure (see Supporting Information).
(4) Catalysis experiments with 10 equiv of CpH showed nearly identical
reactivity profiles as with 15 equiv; slightly diminished activities were
observed with 5 equiv of CpH (70% conv (8 h), cf. 90%).
(5) The enantioselectivities were invariant for each nitrile (98-99% ee)
except for the combination of 1 + 3d, which provided Diels-Alder product
with only 87% ee. The cause of this decreased selectivity is unknown.
evaporation of solvent from a CH2Cl2 solution. Pd-P and
Pd-N bond lengths and P-Pd-P and N-Pd-N bond angles
2+
are similar to those of previously reported P2Pd(NCPh)2
2+
and P2Pd(NCCH3)2 structures.3b,8
728
Org. Lett., Vol. 4, No. 5, 2002

Isolated catalysts 4a and (S)-4c were used for the Lewis
acid catalyzed Diels-Alder reaction. Whereas 4a showed a
significant decrease in activity compared to that of the same
catalyst generated in situ (20% conv, 8 h), (S)-4c displayed
activity comparable to that of the nitrile free catalyst (89%
conv) (Figure 1).9 Complete conversion to Diels-Alder
product was obtained using 2 mol % (S)-4c at -78 °C after
12 h. The product was isolated in 94% yield (97:3 endo/
exo) and 98% ee. The major enantiomer of Diels-Alder
product (2R) is that expected from a (S)-MeObiphepPd2+
fragment.1b
To gain more insight into the relative binding abilities of
the different nitrile ligands to P2Pd2+ the analogous P2Pt-
(NCAr)2(SbF6)2 complexes were generated in situ and the
Pt-P coupling constants measured. In a series of ligands, a
larger JP-Pt is typically associated with a weaker bond trans
to phosphorus,10 and thus a more weakly coordinated nitrile
ligand. Consistent with our original hypothesis, the more
electron-withdrawing nitriles led to larger Pt-P coupling
constants.
Table 2. Comparison of Activity and Enantioselectivity for
Equation 2 as a Function of Catalyst
entrya
catalyst
conv (%)b
% ee
1
2
3
4
5
6
1
55c
81
81
81
81
1 + 3a
1 + 3c
1 + 3d
4a
43c
46c
48c
50 ( 10d
70 ( 10d
(S)-4c
81
a 2 mol % of catalyst, methylene cyclohexane (0.5 mmol,) and ethyl
glyoxylate (1.5 mmol) in 1.5 mL of CH2Cl2, 0 °C. b Conversion for a 5 h
run, measured by GC. c Single experiment. d Average of multiple runs (3+).
less sensitive than that for the Diels-Alder reaction, with
the more electron-withdrawing benzonitriles being only
slightly more active. Isolated catalysts (S)-4c and 4a dis-
played higher reactivity after 5 h ((S)-4c, 70% conv; 4a, 50%
conv) compared to the in situ generated catalysts, though
some variability in conversion was observed (entries 5 and
6). On a preparative scale (1 mmol) the ene product was
obtained in 93% isolated yield using 2 mol % (S)-4c at room
temperature. Ambient temperature was optimal for achieving
>98% conversion to product, though % ee suffered slightly
(80% ee).
Table 1. Comparison of Nitrile Ligand and JP-Pt Coupling
entrya
catalyst
J P-Pt (Hz)
1
2
3
4
5
2 + NCCH3
2 + 3a
2 + 3b
2 + 3c
2 + 3d
3635
3631
3640
3646
3684
The hetero Diels-Alder reaction of phenyl glyoxal and
1,3-cyclohexadiene shown in eq 3 was also investigated.
a NMR experiment; 10 µmol of 2, 25 µmol of AgSbF6, and 20 µmol of
3 in CD2Cl2.
To expand the scope and utility of these catalysts and to
study the effect of nitrile on rate of reaction, we investigated
several other asymmetric transformations known to be
catalyzed by P2Pd2+ Lewis acids such as the glyoxylate-
ene1c,3a and hetero-Diels-Alder reactions.3b
Conditions developed by Oi3b were employed using 2 mol
% catalyst, at 0 °C, in the presence of 4Å MS. As can be
seen in Table 3, reaction conversion was insensititve to the
The glyoxylate-ene reaction in eq 2 was investigated using
Table 3. Comparison of Activity and Enantioselectivity for
Equation 3 as a Function of Catalyst
entrya
catalyst
conv (%)b
% eec
1
2
3
4
5
6
7
1
76d
99
99
99
98
99
1 + 3a
1 + 3b
1 + 3c
1 + 3d
4a
76d
conditions similar to those developed by Mikami,3a but with
only 2 mol % catalyst. As seen in Table 2, the effect of nitrile
on the rate of reaction for in situ generated catalysts was
80d
72d
78d
56 ( 2e
(6) Compound 4a could only be isolated as a crystalline solid when (rac-
MeObiphep)PdCl2 was used; a pure powder was used for the reported
catalysis experiments.
(7) Diels-Alder reactivity and selectivity profiles for (S)-4c after 2
months of benchtop storage were identical to those of freshly prepared
catalyst.
(8) Lindner, E.; Schmid, M.; Wald, J.; Queisser, J. A.; Gepra¨gs, M.;
Wegner, P.; Nachtigal, C. J. Organomet. Chem. 2000, 602, 173-187.
(9) The solubility of (S)-4c is significantly enhanced by the presence of
coordinating substrates.
(S)-4c
55 ( 3e
99
a 2 mol % of catalyst, 1,3-cyclohexadiene (1.0 mmol), and phenyl glyoxal
(0.67 mmol) in 1.0 mL of CH2Cl2, 0 °C. b Conversion for a 5 h run,
measured by GC. c Determined by HPLC. By comparison of the sign of
the rotation3b (S)-4c gives the (+) product, as expected from a (S)-
MeObiphep fragment. d Single experiment. e Average of multiple runs.
(10) (a) Piddcock, A.; Richards, R. E.; Venanzi, L. M. J. Chem. Soc. A
1966, 1707-1710. (b) Appleton, T. G.; Bennett, M. A. Inorg. Chem. 1978,
17, 738-747.
added nitrile after 5 h. Cycloaddition products were consis-
tently obtained with 98-99% ee and a 98:2 diastereomeric
Org. Lett., Vol. 4, No. 5, 2002
729

ratio. Isolated catalysts 4a and (S)-4c were also used for this
transformation. After 5 h with (S)-4c, 55 ( 3% conversion
was observed, with excellent enantioselectivity and diaste-
reoselectivity, and 56 ( 2% conversion was observed with
4a. On a preparative scale, after 48 h using 2 mol % (S)-4c,
88% conversion was achieved. Pure product could be isolated
after column chromatography in 85% yield with 99% ee and
a 98:2 diastereomeric ratio.
Table 4. Comparison of Activity and Enantioselectivity for
Equation 4 as a Function of Catalyst
entrya
catalyst
conv (%)b
% eec
1
2
3
4
5
6
7
1
54d
99
99
98
99
98
1 + 3a
1 + 3b
1 + 3c
1 + 3d
4a
68d
61d
66d
64d
The hetero-Diels-Alder reaction of ethyl glyoxylate and
1,3-cyclohexadiene was also investigated, eq 4. Conditions
63 ( 11e
(S)-4c
54 ( 2e
99
a 2 mol % of catalyst, 1,3-cyclohexadiene (0.68 mmol), and ethyl
glyoxylate (2.93 mmol) in 1.0 mL of CH2Cl2, 0 °C. b Conversion for a 5 h
run, measured by GC. c Determined by GC. By comparison of the sign of
the rotation,3b (S)-4c gives the (3R) product. d Single experiment. e Average
of multiple runs.
cases shows enhanced activity compared to traditional
benzonitrile- and acetonitrile-stabilized dications.
developed by Oi,3b employing 2 mol % catalyst were used.
In situ generated catalysts showed 56-69% conversion after
5 h with no apparent correlation to nitrile, Table 4. In situ
and isolated catalysts produced cycloadducts with 98-99%
ee and a 98:2 diastereomeric ratio. After 5 h, only 55 ( 3%
conversion to products was observed. Similarly, 4a provided
only 56 ( 2% conversion after 5 h. On a preparative scale,
after 24 h, complete conversion was obtained and pure
product could be isolated in 83% yield and 99% ee (99:1
endo/exo).
Acknowledgment. This work was partially supported by
NIGMS (RO1 GM60758-01), the Petroleum Research Fund,
DuPont, and Union Carbide. M.R.G. is a Camille Dreyfus
Teacher Scholar (2000).
Supporting Information Available: Experimental pro-
cedures, spectroscopic and analytical data for 4a and (S)-
4c, and crystallographic data collection parameters and
metrical parameters for (R)-4c. This material is available free
of charge via the Internet at http://pubs.acs.org.
In summary, we have successfully developed a new bench-
stable Lewis acid catalyst that demonstrates a reactivity
profile similar to unstabilized P2Pd2+ catalysts, and in some
OL017218Q
730
Org. Lett., Vol. 4, No. 5, 2002