A polymer-supported phosphoramide as a Lewis-base catalyst for the catalytic aldol reaction

Article abstract of DOI:10.1002/ejoc.200400228

The aldol reactions between trichlorosilyl enol ethers and aldehydes were catalyzed by an environmentally benign polymer-supported phosphoramide organocatalyst. Eight examples are reported with moderate to good chemical yields and stereoselectivity. Signi

Full text of DOI:10.1002/ejoc.200400228

SHORT COMMUNICATION
A Polymer-Supported Phosphoramide as a Lewis-Base Catalyst for the
Catalytic Aldol Reaction
[a]
[b]
[b]
[b]
Robert A. Flowers II,* Xin Xu, Cody Timmons, and Guigen Li*
Keywords: HMPA-type derivative / Aldol reactions / Polymeric phosphoramide
The aldol reactions between trichlorosilyl enol ethers and
yields and stereoselectivity. Significant rate enhancements
aldehydes were catalyzed by an environmentally benign were observed.
polymer-supported phosphoramide organocatalyst. Eight
examples are reported with moderate to good chemical
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
Hexamethylphosphoric triamide (HMPA) has been ex-
tensively used as a reagent in organic chemistry because of
[
1,2]
its superior solvation and coordination properties.
In
fact, HMPA is among the most useful organic reagents for
[3]
a variety of reactions such as aldol reactions, vinyl anionic
[
4]
[5]
enolate alkylations,[6] oxi-
Scheme 1
additions,
allylations,
[
7]
[8]
dations, 1,4-conjugate additions, ylide-based CϭC bond
[
9]
formations, and various transition-metal-catalyzed reac- be extended to polymer-bound phosphoramides as catalysts
[
10]
tions.
Unfortunately, HMPA is also toxic and has been for asymmetric reactions.
identified as a potential carcinogenic reagent. This limits its
broad utility in organic synthesis.
Initial studies were carried out on the reaction of the
trichlorosilyl enol ether of cyclohexanone and benzaldehyde
at Ϫ78 °C in the presence of 10 mol % of PS-phosphoram-
ide. The reaction was complete within three hours and af-
forded a chemical yield of 80 % and a diastereoselectivity
of 1:1. The PS-phosphoramide catalyst clearly plays an im-
portant role in the reaction, as nearly no product was
formed at this temperature in the absence of a catalyst.[
When the reaction temperature was increased to Ϫ23 °C,
the reaction-completion time was shortened to two hours,
and the diastereoselectivity was improved to 9:1 (syn/anti).
Furthermore, increasing the amount of catalyst resulted in
meaningful improvement on reaction efficiencies. As a re-
sult of this initial investigation, the aldol reaction of other
aromatic aldehydes were examined and the results are sum-
marized in Table 1.
Results and Discussion
To address the toxicity problems of HMPA, while main-
taining its excellent synthetic utility, we attempted to make
a polymer-supported HMPA-type derivative (PS-phos-
13]
[
11,12]
phoramide)
and to examine its use as a catalyst. In this
communication, we report the first application of an
HMPA-type moiety-derived polymer as the catalyst in an
aldol reaction of the trichlorosilyl enol ether of cyclohexa-
none with a variety of aldehydes (see Scheme 1).
The use of phosphoramides as catalysts in the addition
of trichlorosilyl enol ethers to aldehydes provides a useful
method for the synthesis of β-hydroxy ketones.[2] We rea-
soned that if the present protocol was successful, it could
It is interesting to note that the current PS-phosphoram-
ide-catalyzed aldol reaction results in aldol products with
an opposite configuration to that of the products obtained
by reactions with homogeneous, chiral phosphoramide
[
a]
Department of Chemistry, Lehigh University,
Bethlehem, PA 18015, USA
[
2a]
catalysts.
These products were, in fact, found to be the
E-mail: rof2@lehigh.edu
[
b]
same as for the uncatalyzed aldol reaction at the higher
Department of Chemistry and Biochemistry, Texas Tech
University,
temperature where syn isomers dominated over the anti iso-
Lubbock, TX 79409-1061, USA
E-mail: guigen.li@ttu.edu
[13]
mers. This observation suggests that the present aldol re-
action could proceed through two possible pathways. The
first possible pathway potentially involves the formation of
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
2988
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400228
Eur. J. Org. Chem. 2004, 2988Ϫ2990

A Polymer-Supported Phosphoramide
SHORT COMMUNICATION
Table 1. Results of the PS-phosphoramide-catalyzed aldol reaction of the unprotected aminomethyl resin SS. In order to
study the effectiveness of PS-phosphoramide as a reusable
organocatalyst, a portion of the catalyst was recovered and
reused in several consecutive trials. It was found that the
polymer could be reused, however, its effectiveness was
somewhat diminished (about 15 % lower then the original
reaction). The diminished catalytic activity is presumably
due to slow destruction of the polymer when subjected to
the vigorous stirring of a magnetic stir bar. One might ex-
pect better results if the reaction were agitated with a shaker
as opposed to a magnetic stirrer.
Entry R
Product[14] Time, h syn/anti[a] Yield, %[b]
1
2
3
4
5
6
7
8
Ph
p-OMeC
p-FϪC
p-ClC
p-BrC
p-NO
1-Naphthyl
3,4-(CH
1
2
3
4
5
6
7
8
2
2
2
2
2
6
6
2
9:1
5:1.1
4:1
3:1
4:1
10:1
0.9:1
6.3:1
83
64
82
79
85
66
65
71
6
H
H
4
4
In conclusion, the first polymer-supported, phosphoram-
ide-catalyzed aldol reaction of a trichlorosilyl enol ether
with aldehydes was successfully developed with significant
rate enhancements at low temperature. Moderate to good
yields and diastereoselectivities were obtained for eight ex-
amples. Compared to homogeneous phosphoramides, this
new heterogeneous biphasic approach is potentially safer
and shows promise for use as a recyclable catalyst. Efforts
to develop chiral, polymer-supported phosphoramides for
a catalytic asymmetric version of this reaction are currently
in progress.
6
H
6
4
H
6
4
2
C
6
H
4
3 2 6 4
) C H
[
a]
Estimated by crude H NMR determination. [b] Isolated yield of
1
pure product after purification by flash chromatography; typical
procedure was provided in ESI.
a pre-aldol complex which is responsible for an open-chain
mechanism. The second possible mechanism could poten-
tially involve a closed, boat-like transition state. We propose
that the first hypothesis is more likely, due to the bulky
environment on the polymer. This hypothesis can be in-
directly supported by the fact that Denmark’s bulky, chiral
phosphoramide catalyst resulted in the prevalent syn selec-
Experimental Section
1
. Procedure for the Synthesis of PS-Phosphoramide: A resin
aminomethyl resin SS purchased from Advanced ChemTech,
44 mg, 0.171 mmol) and fresh CDCl (3 mL) were added into a
dry vial. The mixture was stirred slowly at room temperature, and
then K CO (310 mg), DMAP (15 mg), Et N (0.6 mL), and do-
(
2
3
[
13]
tivity.
It should be pointed out that at Ϫ23 °C, the reaction can
2
3
3
occur in the absence of PS-phosphoramide catalyst to give decane (0.375 mmol, 64 mg, as internal standard material for NMR
the aldol product in 67 % yield with a diastereoselectivity measurement) were added. Finally, tetramethylphosphorodiamidic
of 50:1 (syn/anti). Interestingly, the syn/anti stereoselectivity chloride (1.85 mmol, 316 mg, 10Ϫ11 equiv.) was added to the
above mixture. The reaction proceeded for five days, when tetra-
methylphosphorodiamidic chloride remained constant, as revealed
changes during the reaction process from 20:1 to 50:1 over
1
hour. After the first hour, this ratio remained unchanged
1
by direct NMR determination. The polymer resin was finally fil-
tered, washed five times with CHCl and dried under vacuum.
as monitored by H NMR analysis. The reaction was obvi-
ously accelerated by the presence of the PS-phosphoramide
3
catalyst. Meanwhile, the yield also increased, albeit the syn/ 2. Typical Procedure for Aldol Reaction: Polymer-supported phos-
anti stereoselectivity was decreased by a factor of 5 (see phoramide (150 mg) and silyl enol ether (232 mg, 1.0 mmol) were
Table 2).
loaded onto an oven-dried vial. The vial was flushed with nitrogen
and cooled to Ϫ23 °C. Freshly distilled dichloromethane (5 mL)
was added and the resulting heterogeneous mixture was allowed to
stir for 5 minutes before adding aldehyde (2 mmol) dropwise with
a syringe over a period of one minute. The reaction was allowed to
stir undisturbed for 2 hours, at which time it was quenched with
saturated aqueous sodium hydrogencarbonate solution. The re-
sulting biphasic system was extracted with dichloromethane (3 ϫ
Table 2. Effects of the PS-phosphoramide catalyst on the rate and
selectivity of the aldol reaction
Yield[a] (selectivity[b]
)
Catalyst loading
0.5 h
17 (20:1)
30 (4:1)
1 h
35 (50:1)
55 (8:1)
2 h
67 (50:1)
83 (9:1)
10 mL), washed with brine, dried over anhydrous sodium sulfate,
0
1
%
0 %
and concentrated under reduced pressure. Flash chromatography
on silica gel (EtOAc/hexane, 1:5) afforded the pure products.
[
a]
The reaction was incomplete except for the cases of a 2 h period;
[b]
isolated yield after flash chromatography. Estimated selectivities
1
by crude H NMR determination.
Acknowledgments
We gratefully acknowledge NIH (CA, 99995-1, GL) and the
Robert A. Welch Foundation (D-1361, GL), NSF (CHE-0413845,
It is very interesting to find that the trichlorosilyl enol
ether is resistant to reaction with the HϪN moiety on the
polymer bead under the current conditions. We also found RAF) for the generous support of this work. The partial funding
that the aldol reaction proceeded smoothly in the presence of the 500 MHz NMR spectrometer was supported by NSF.
Eur. J. Org. Chem. 2004, 2988Ϫ2990
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2989

R. A. Flowers II, X. Xu, C. Timmons, G. Li
SHORT COMMUNICATION
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2990
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2988Ϫ2990