Bicarbonate Salts as Cost-Effective Bases for the Synthesis of Ketenes and Their Synthetic Equivalents Applied to the Asymmetric Synthesis of β-Lactams

Article abstract of DOI:10.1055/s-2003-41497

We report the use of bicarbonate salts as viable alternatives to more expensive bases for the in situ generation of ketenes and their synthetic equivalents. We have successfully applied this to the catalytic, asymmetric synthesis of β-lactams.

Full text of DOI:10.1055/s-2003-41497

CLUSTER
1937
Bicarbonate Salts as Cost-Effective Bases for the Synthesis of Ketenes
and Their Synthetic Equivalents Applied to the Asymmetric Synthesis
of b-Lactams
Bicarbonate Salts for
t
e
he Synthesi
h
s
of
K
etenesa H. Shah, Stefan France, Thomas Lectka*
Department of Chemistry, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA
Fax +1(410)5168420; E-mail: lectka@jhu.edu
Received 27 June 2003
or their synthetic equivalents in situ for use in the
Abstract: We report the use of bicarbonate salts as viable
alternatives to more expensive bases for the in situ generation of
ketenes and their synthetic equivalents. We have successfully
applied this to the catalytic, asymmetric synthesis of b-lactams.
catalytic,
asymmetric
synthesis
of
b-lactams
(Equation 1).8 The procedure, which we report herein,
involves the cinchona alkaloid derivative benzoylquinine
(3a) and is operationally very simple, cost-effective and
has been demonstrated in the synthesis of a variety of b-
lactam products.
Key words: b-lactam, bicarbonate salts, asymmetric catalysis,
cinchona alkaloids
A long-standing problem in ketene chemistry has been to
utilize the reactive character of pure monosubstituted
ketenes for synthetic purposes without having to go
through laborious procedures for their synthesis.1 To date,
reactive monosubstituted ketenes are most commonly
made in situ from acid chlorides through trialkylamine-
promoted dehydrohalogenation reactions.2 For many
purposes, this procedure works very well, but in other
cases, the trialkylamine can effect undesired side
reactions.3 Along those lines, we have sought alternative
ways to make solutions of ketenes or their synthetic
equivalents in situ. Previous work has shown that
homogeneous bases (proton sponge,4 the phosphazine
base BEMP) as well as heterogeneous bases (K2CO3,5
NaH,6 or the resin-bound variant of BEMP7) promote the
formation of reactive ketenes from the corresponding acid
chlorides effectively. However, each of these variants,
while suited for particular purposes, does not provide a
universal solution to the problem of clean ketene
generation.
Equation 1
At the outset, the crucial consideration for us was the
expected stoichiometric reaction of NaHCO3, for
example, with the HCl produced from acid chloride
dehydrohalogenation. This reaction should produce NaCl,
and more importantly, carbonic acid, which readily
dissociates to form CO2 and water (Scheme 1). Water is
expected to be deleterious to the reaction; however, if it is
effectively sequestered by employing NaHCO3 as a
drying agent then we would eliminate this concern. This
is indeed what we found in practice by using an excess of
NaHCO3 (> 15 equiv). In theory, the mechanism could
proceed through one of two pathways: 1) formation of the
zwitterionic enolate from attack by BQ on free ketene 4
or, 2) enolate formation from the deprotonation of the acyl
ammonium salt.
The major drawback with the homogeneous bases lies
with cost. While proton sponge is moderately priced,
BEMP is very expensive.6 To improve cost, we developed
procedures using NaH and K2CO3. Both are inexpensive
bases, however each has important disadvantages. NaH is
extremely hygroscopic and proper precautions must be
taken for its use. With K2CO3, a specialized dual reaction
vessel is necessary to separate the ketene formation and
ketene utilization steps.4 Among other reasons, K2CO3 has
a tendency to racemize or epimerize products, and thus it
must be separated out before subsequent chemistry can be
accomplished. Recently, we made the somewhat
surprising observation that bicarbonate salts can
effectively act as stoichiometric bases to produce ketenes
In order to indicate the potential reaction pathway, we
designed an experiment to determine the temperature
threshold of the bicarbonate reaction. Due to thermal
instability of monosubstituted ketenes they are normally
generated in situ at low temperatures. In our previous
work with NaH and K2CO3, we found that cooling our
SYNLETT 2003, No. 12, pp 1937–1939
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Advanced online publication: 19.09.2003
DOI: 10.1055/s-2003-41497; Art ID: S07203ST
© Georg Thieme Verlag Stuttgart · New York

1938
M. H. Shah et al.
CLUSTER
CH3CN, we were only able to obtain trace amounts of the
b-lactam.
Table 2 Solvent Effects on b-Lactam Formation
Entry
Solvent
Toluene
THF
Yield (%)a
eeb
92
70
65
–
drc
12:1
8:1
5:1
1:1
–
1
2
58
50
3
CH2Cl2
CH3CN
DMSO
26
4
15
5d
trace
–
a Isolated yield after column chromatography.
Scheme 1 Mechanism of b-lactam formation with NaHCO3
b Enantioselectivity of cis enantiomer determined by chiral HPLC.
c Cis/trans ratio determined via 1H NMR of the crude residue.
d Reaction performed at r.t.
reaction flasks to –78 °C allowed for the ketene formation.
Under our published conditions, most ketenes do not give
significant amounts of the desired products when the
reactions are performed above –10 °C.1 Also, extended
ketene formation times are often necessary at these lower
temperatures. Surprisingly, when phenylacetyl chloride is
employed with NaHCO3, b-lactam 5a is formed in 58%
yield with a 3:1 cis/trans ratio and 55% ee (R,R) at room
temperature. Since phenylketene is not stable at room
temperature, we can conclude that significant quantities of
free ketene must not be present in solution, and therefore
at this time pathway 2 is the more likely mechanism.
With the optimal cation and solvent for the reaction
determined, we screened a number of acid chlorides in the
reaction with N-tosyl imino ester, 10 mol% BQ, 15
equivalents of NaHCO3, and 10 mol% 15-crown-5 at –10
°C over 5 hours and successfully synthesized a variety of
b-lactams (Equation 2, Table 3).
In order to determine the optimal reaction conditions, we
began to look at other bicarbonate salts. We screened the
other available alkali metal bicarbonates and compared
their activity (Table 1). These reactions were performed
with a cat. amount of a crown ether to sequester the metal
cations and enhance solubility. While the salts gave
comparable yields, enantioselectivity and diastereo-
selectivity were seriously lowered with the potassium (6:1
dr, 72% ee) and cesium salts (4:1 dr, 65% ee) as compared
to the sodium ones (12:1 dr, 92% ee).
Equation 2
Table 3 b-Lactam synthesis using NaHCO3
Entry Acid chloride
Product
Yield eeb drc
(%)a
Table 1 Effects of Alkali Metal Cation on b-Lactam Formation
1
58
40
52
48
92 12:1
89 10:1
88 11:1
84 10:1
Entry
Bicarbonate Yield (%)a
eeb
92
72
65
drc
12:1
6:1
1a
5a
5b
5c
5d
1
2
3
NaHCO3
KHCO3
CsHCO3
58
58
50
2
4:1
1b
a Isolated yield after column chromatography.
b Enantioselectivity of cis enantiomer determined by chiral HPLC.
c Cis/trans ratio determined via 1H NMR of the crude residue.
3
1c
We also examined the effects of the solvent on the
formation of b-lactam product (Table 2). We looked at
aprotic solvents ranging in polarity and solubility, each
with NaHCO3 salt. Generally, toluene was found to be the
best solvent for this reaction. Although THF was fairly
comparable in terms of yield, a considerable drop in
diastereoselectivity was observed with its use.
Surprisingly, with more polar solvents like DMSO and
4
1d
a Isolated yield after column chromatography.
b Enantioselectivity of cis enantiomer determined by chiral HPLC.
c Cis/trans ratio determined via 1H NMR of the crude residue.
Synlett 2003, No. 12, 1937–1939 © Thieme Stuttgart · New York

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Bicarbonate Salts for the Synthesis of Ketenes
1939
We were successfully able to obtain b-lactam products
from aryl acid chlorides like phenylacetyl chloride in 58%
yield with 12:1 dr and 92% ee (entry 1). Furthermore, oxo
acid chlorides are highly compatible with this methodolo-
gy. Phenoxyacetyl chloride 1b gave the corresponding b-
lactam 5b in 89% ee with 10:1 dr (entry 2). Benzyloxy-
acetyl chloride 1c gave b-lactam 5c with 11:1 dr and 88%
ee (entry 3).
Acknowledgment
T. L. thanks the NIH, the Sloan and Dreyfus Foundations, and
Merck & Co. for support. S. F. thanks the UNCF, Merck and Pfizer
for graduate fellowships.
References
(1) (a) Tidwell, T. T. Ketenes; John Wiley & Sons: New York,
1995. (b) Tidwell, T. T. Acc. Chem. Res. 1990, 23, 273.
(2) (a) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M.
Eur. J. Org. Chem. 1999, 3223. (b) Lynch, J. E.; Riseman,
S. M.; Laswell, W. L.; Tschaen, D. M.; Volante, R. P.;
Smith, G. B.; Shinkai, I. J. Org. Chem. 1989, 54, 3792.
(3) Hegedus has found that trialkylammonium salts can
interfere with the diastereoselectivity of the Staudinger
reaction to produce b-lactams: Hegedus, L. S.; Montgomery,
J.; Narukawa, Y.; Snustad, D. C. J. Am. Chem. Soc. 1991,
113, 5784.
(4) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W.
J. III; Lectka, T. J. Am. Chem. Soc. 2000, 122, 7831.
(5) Hafez, A. M.; Taggi, A. E.; Wack, H.; Esterbrook, J.; Lectka,
T. Org. Lett. 2001, 3, 2049.
(6) Taggi, A. E.; Wack, H.; Hafez, A. M.; France, S.; Lectka, T.
Org. Lett. 2002, 4, 627.
(7) (a) Hafez, A. M.; Taggi, A. E.; Lectka, T. Chem.–Eur. J.
2002, 8, 4114. (b) Hafez, A. M.; Taggi, A. E.; Dudding, T.;
Lectka, T. J. Am. Chem. Soc. 2001, 123, 10853. (c) Wack,
H.; Taggi, A. E.; Hafez, A. M.; Drury, W. J. III; Lectka, T.
J. Am. Chem. Soc. 2001, 123, 1531. (d) Hafez, A. M.;
Taggi, A. E.; Wack, H.; Drury, W. J. III; Lectka, T. Org.
Lett. 2000, 2, 3963.
(8) (a) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.;
Ferraris, D.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 6626.
(b) Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc. Chem. Res.
2003, 36, 10. (c) France, S.; Wack, H.; Hafez, A. M.; Taggi,
A. E.; Witsil, D. R.; Lectka, T. Org. Lett. 2002, 4, 627.
(d) Dudding, T.; Hafez, A. M.; Taggi, A. E.; Wagerle, T. R.;
Lectka, T. Org. Lett. 2002, 4, 387. (e) Hafez, A. M.;
Dudding, T.; Wagerle, T. R.; Shah, M. H.; Taggi, A. E.;
Lectka, T. J. Org. Chem. 2003, 68, 5819.
While the conditions worked for most acid chlorides, they
did not seem to work well for less acidic ones like phenox-
ypropionyl chloride. To remedy this issue, we further
cooled the reaction to –40 °C and obtained the b-lactam
5d in 48% yield with 10:1 dr and 84% ee (entry 4).
In summary, we have developed a cost-effective, catalytic
asymmetric synthesis of b-lactams using NaHCO3 to gen-
erate ketenes and their synthetic equivalents without the
need for specialized equipment or anhydrous conditions.
Furthermore, we improved on our previously published
methods by simplifying the synthetic procedure. The
bicarbonate salts were found to be cheaper and easier to
use than other bases we have tried as suitable alternatives.
This method is amenable to aryl, alkyl and oxo acid
chlorides and we are confident that this methodology will
be applicable to other substituted acid chlorides.
General Procedure for b-Lactams using NaHCO3. To a vigor-
ously stirred solution of NaHCO3 (350 mg, 4.01 mmol), BQ (6 mg,
0.0129 mmol), and 15-crown-5 (3 mg, 0.0129 mmol) in toluene (6
mL) at –40 °C, phenylacetyl chloride 1 (20 mg, 0.129 mmol) in tol-
uene (1 mL) at –40 °C was added dropwise followed by a-imino es-
ter 2 (33 mg, 0.129 mmol) in toluene (2 mL). The reaction was
allowed to stir for 5 h as it slowly warmed to r.t. The reaction mix-
ture was washed with 1 M HCl, extracted with CH2Cl2 (3 × ). The
organics were combined and dried with MgSO4. The solvent was re-
moved under reduced pressure and the crude mixture was subjected
to column chromatography (15% EtOAc–hexanes) on a plug of sil-
ica gel to yield 5a (58% yield, 28 mg).
All b-lactams synthesized have been characterized in previous work
and all analytical data were consistent with published results.8
Synlett 2003, No. 12, 1937–1939 © Thieme Stuttgart · New York