Scheme 1. Relay Deprotonation with Carbonate Salts
Scheme 2. Dual Reaction/Filtration Flask
Carbonate salts are very inexpensive commodity chemi-
cals,5 have low toxicity, and are easy to dispose of after use.
Because of their insolubility in organic media, there exists
precedent for their use as stoichiometric bases in phase
transfer reactions.6 Scheme 1 shows how the shuttle depro-
tonation system works. Fine mesh K2CO3 is in contact with
an organic phase (e.g., toluene solvent at -78 °C), in which
are dissolved an acid chloride 1 and a small amount of a
chiral nucleophilic catalyst (e.g., benzoylquinine 3) that
doubles as a shuttle base. After 12 h, the preponderance of
acid chloride is consumed and replaced by a solution of the
putative ketene.
Precisely how the catalytic shuttle base effects mono-
substituted ketene formation is not known at the moment;
however, two subtly different mechanisms come to mind.
The first involves direct deprotonation of acylammonium salt
3a by carbonate with attendant elimination of the catalyst 3.
The second mechanism involves formation of the hydro-
chloride salt 3b through acid chloride dehydrohalogenation
and subsequent deprotonation of 3b to regenerate 3. In either
case, the catalyst (or its derived complexes) serve as effective
proton “shuttles” for ketene formation. Byproduct bicarbon-
ate and alkali metal halides then precipitate. Once the ketene
has formed stoichiometrically, it can easily be separated from
the solid phase by filtration if necessary.
linked by a fritted disk. The disk is located as low as possible
in the assembly to allow it to be conveniently submerged in
a cold bath. By canting the assembly in one direction, the
reaction liquor can be transferred from one side to another
without removing the piece from the bath, thus preserving
the thermally unstable monosubstituted ketenes and leaving
product salts and unreacted carbonate behind.
With an efficient in situ synthesis in hand, we turned our
attention to catalytic asymmetric ketene brominations, screen-
ing a number of reagents for this purpose (NBS, an obvious
choice, is inactive in these applications).8 We found that the
polybrominated p-quinone 2,4,4,6-tetrabromo-2,5-cyclohexa-
dien-1-one 4 works best in the reaction (eq 1). The
brominating agent 4, which is commercially available, is also
easily and inexpensively made in gram quantities by treat-
ment of 2,4,6-tribromophenol with Br2 in acetic acid in 90%
yield. It is stable for extended periods when stored under
N2 in a refrigerator.
In our preliminary report on catalytic chlorinations, we
proposed that the reaction proceeds through intermediate
ketenes formed from dehydrohalogenation reactions using
proton sponge3 or a highly basic resin (BEMP)9 as a base.
In the interim, we identified two factors that would improve
the utility and economy of the proposed reactions. The first
was to substitute less expensive carbonate salts for the
original dehydrohalogenating base (5 g of BEMP costs about
We have designed a simple piece of glassware to facilitate
the ketene generation experiment and subsequent filtration
(Scheme 2).7 The apparatus consists of two recovery flasks
(7) This flask will soon be commercially available from ChemGlass.
(8) (a) Bright, R.; Freeman, S.; Hayes, D.; Smith, G.; Tapolczay, D.;
Coote, S. J. Synth. Comm. 1996, 26, 4195-4209. (b) Khan, G, R.; Leahy,
D. E.; Katrizky, A. R. J. Org. Chem. 1984, 49, 4784-4786.
(9) (a) Hafez, A. M.; Taggi, A. E.; Wack, H. W.; Drury, W. J., III; Lectka,
T. Org. Lett. 2000, 2, 3963-3965. (b) Schwesinger, R.; Willaredt, J.;
Schempler, H.; Keller, M.; Schmitt, D.; Fritz, H. Chem. Ber. 1994, 127,
2435-2454.
(5) Fine mesh size K2CO3 is available from Aldrich and several other
companies.
(6) (a) Nelson, A. Angew. Chem., Int. Ed. 1999, 38, 1583-1585. For
other dual uses of amine/carbonate base systems, see: (b) Tanabe, Y.;
Yamamoto, H.; Yoshida, Y.; Miyawaki, T.; Utsumi, N. Bull. Chem. Soc.
Jpn. 1995, 68, 297-300. (c) Sasson, Y.; Bilman, N. J. Chem. Soc., Perkin
Trans. 2 1989, 2029-2033.
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Org. Lett., Vol. 3, No. 13, 2001