A R T I C L E S
Taggi et al.
Scheme 3. Shuttle Deprotonation with Kinetic and
Thermodynamic Bases
they are invariably stirred with precipitated and partially
dissolved ammonium salt byproducts.28 In some cases, the
presence of these trialkylammonium byproducts presents no
problem. However, we found that in many instances (vide infra),
trialkylammonium salts were deleterious to established reac-
tions.29 Trialkylammonium salts have an appreciable solubility
in almost all organic solvents and can serve as unwanted
Brønsted acid catalysts. They are in equilibrium with the
corresponding free amine bases that can act as nucleophiles or
ligands; and because they are achiral, they may interfere with
the desired reaction, producing racemic products.
One possible solution is to use polymer-bound bases such as
the highly basic resin BEMP 3a,30 a triaminophosphonamide
imine bound to a polymeric support,31 to form ketenes 2 from
acid halides 1.32 We found that BEMP produces many ketenes
rapidly when THF solutions of suitable acid chlorides 1 are
passed through an addition funnel at -78 °C containing the
polymer (eq 2).33,34 Alternatively, the BEMP polymer can be
Our first approach to the shuttle base synthesis of ketenes in
situ was the use of the strong organic base proton sponge (3b)
as a nonnucleophilic thermodynamic base. We found that simply
mixing 1 equiv of 3b and acid chlorides 1 at low temperature
usually does not produce detectable amounts of ketene. Although
3b is a strong thermodynamic base, it is hindered and in most
cases kinetically slow at deprotonating carbon-based acids.37
We found that a nucleophile such as benzoylquinine (BQ,
4a), an inexpensive38 and versatile asymmetric catalyst,39 serves
as an excellent shuttle base (base k) when added to a solution
of various acid chlorides 1 in toluene at low temperature. In
the case of diphenylketene 2b, a yellow solution is formed along
with a white precipitate over the course of a few minutes.40 In
an appropriate solvent like toluene, the ammonium salt of proton
sponge was found to not interfere in many asymmetric reactions
catalyzed by chiral nucleophiles. The main drawbacks to the
use of the proton sponge-shuttle procedure include economical
aspects (although proton sponge is a moderately priced chemical,
in large quantities its use may be a cost factor) as well as the
possibility that in rare instances the sponge itself may react in
undesirable ways.33
added to a solution of the acid chloride at low temperature. After
a few minutes, filtration of the solid-supported base produces
the desired solution of pure ketene. We previously investigated
other polymer-supported bases such as guanidines and tertiary
amines but found them to be ineffective for ketene generation.35
Although they are attractive reagents, the primary drawback to
the use of polymeric bases involves their expense (5 g of BEMP
costs about $120).
Shuttle Deprotonation. The use of tertiary amines for
dehydrohalogenations of acid halides 1 to form ketenes for our
reactions is complicated by the fact that they are usually too
nucleophilic. The use of a stoichiometric base that is thermo-
dynamically strong, but kinetically nonnucleophilic, could
overcome this problem. This strategy, which we term “shuttle
deprotonation”, utilizes a catalytic, chiral nucleophile, which
is kinetically active (base k), to dehydrohalogenate the acid
chloride in the first step (Scheme 3). Exploiting the premise
that proton transfers between heteroatoms are inherently fast,36
the kinetically favored base k then rapidly transfers its proton
to base t, the thermodynamically active, but kinetically restricted
base, to regenerate itself for another catalytic cycle.
Carbonate and Hydride Shuttle Bases. We have also looked
at powdered carbonates as stoichiometric heterogeneous bases
(37) Remarkably, there are some cases where the R-proton of the acid chloride
is acidic enough to make it possible for proton sponge to perform the
dehydrohalogenation without the assistance of BQ. See: Tidwell, T. T.;
Fenwick, M. H. Eur. J. Org. Chem. 2001, 3415-3419.
(38) Multigram quantities of benzoylquinine are easily synthesized in one step
from benzoyl chloride and quinine. Also, BQ is benchtop stable indefinitely.
(39) Cinchona alkaloids have the status as general nucleophilic catalysts and
ligands for many organic reactions, for example see: (a) McDaid, P.; Chen,
Y.; Deng, L. Angew. Chem., Int. Ed. 2002, 41, 338-340. (b) Hang, J.;
Tian, S.-K.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2001, 123, 12696-
12697. (c) Bolm, C.; Schiffers, I.; Dinter, C. L.; Defre`re, L.; Gerlach, A.;
Raabe, G. Synthesis 1719-1730. (d) Kacprzak, K.; Gawronski, J. Synthesis,
2001, 7, 961-998. (e) Bolm, C.; Schiffers, I.; Dinter, C. L.; Gerlach, A. J.
Org. Chem. 2000, 65, 6984-6991. (f) Zhang, F.-Y.; Corey, E. J. Org. Lett.
2000, 2, 1097-1100. (g) Alvarez, R.; Hourdin, M.-A.; Cave, C.; d’Angelo,
J.; Chaminade, P. Tetrahedron Lett. 1999, 40, 7091-7094. (h) Martyres,
D. Synlett 1999, 9, 1508-1515. (i) Studer, M.; Blaser, H.-U.; Okafor, V.
J. Chem. Soc., Chem. Commun. 1998, 9, 1053-1054. (j) Corey, E. J.; Noe,
M. C.; Grogan, M. J. Tetrahedron Lett. 1996, 37, 4899-4902. (k) Kolb,
H. C.; Andersson, P. G.; Sharpless, K. B. J. Am. Chem. Soc. 1994, 116,
1278-1291. (l) Wang, L.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114,
7568-7570. (m) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103,
417-430.
(28) Even after filtration, solubilized salts may remain.
(29) Hegedus has found that trialkylammonium salts can interfere with the
diastereoselectivity of the Staudinger reaction to produce â-lactams:
Hegedus, L. S.; Montgomery, J.; Narukawa, Y.; Snustad, D. C. J. Am.
Chem. Soc. 1991, 113, 5784-5791.
(30) The pKa of the conjugate acid of BEMP in DMSO is 16.2. See: O’Donnell,
M. J.; Delgado, F.; Hostettler, C.; Schwesinger, R. Tetrahedron Lett. 1998,
39, 8775-8778.
(31) Schwesinger, R.; Willaredt, J.; Schlemper, H.; Keller, M.; Schmitt, D.; Fritz,
H. Chem. Ber. 1994, 127, 2435-2454.
(32) Hafez, A. M.; Taggi, A. E.; Wack, H.; Drury, W. J., III; Lectka, T. Org.
Lett. 2000, 2, 3963-3965.
(33) Wack, H.; Taggi, A. E.; Hafez, A. M.; Drury, W. J., III; Lectka, T. J. Am.
Chem. Soc. 2001, 123, 1531-1532.
(34) For scaled up reactions, mechanical agitation of the polymer in the addition
funnel is beneficial.
(35) Hafez, A. M.; Taggi, A. E.; Dudding, T.; Lectka, T. J. Am. Chem. Soc.
2001, 123, 10853-10859.
(40) Tidwell has recently used our proton sponge shuttle base methodology to
observe and study the reactivity of bisketenes: Allen, A. D.; Fenwick, M.
H.; Jabri, A.; Rangwala, H.; Saidi, K.; Tidwell, T. T. Org. Lett. 2001, 3,
4095-4098.
(36) (a) Bell, R. P. The Proton in Chemistry; Cornell University Press: Ithaca,
NY, 1973. (b) For discussions concerning proton sponge basicity, see:
Alder, R. W. Chem. ReV. 1989, 89, 1215-1270.
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6628 J. AM. CHEM. SOC. VOL. 124, NO. 23, 2002