synthesis in the ease of reaction workup and product
purification with the additional advantages associated with
traditional solution phase synthesis.7 Owing to the nature of
the heterogeneous reaction conditions, however, most scav-
enging protocols require long reaction times, therefore
potentially minimizing the benefits of any preceding high-
speed microwave-assisted synthesis steps.
We here describe the application of controlled microwave
heating for the rapid and selective scavenging of both excess
reactants and unwanted byproducts in the preparation of an
N3-acylated dihydropyrimidine library, applying both sup-
ported and unsupported nucleophilic scavenger agents.
Results and Discussion. In recent work, we have reported
the solution-phase generation of a diverse library of multi-
functionalized dihydropyrimidines (DHPMs) via automated
robotic microwave-assisted synthesis, employing a modified
Biginelli multicomponent condensation protocol.6 Since most
of the pharmacologically attractive DHPM derivatives are
N3-acylated analogues,8 we became interested in developing
a rapid method for accessing libraries containing this
structural motif in high-throughput format.
was also formed applying these forcing conditions (only ca.
1% of bis-acetylated product 3Aa was produced using Ac2O
at 130 °C/10 min).
2. Microwave-Assisted Scavenging. While the N3-
acetylated DHPM 2Aa could by isolated in near-quantitative
yield and >98% purity by a simple evaporative workup, it
was evident that other, less volatile anhydrides would require
a more elaborate workup method to make the acylation
protocol amenable to a high-throughput format. We have
therefore employed the supported nucleophilic scavenging
reagents 4 and 5 in our studies in order to quench excess
anhydride from the reaction mixture. While the polymer-
supported ethylenediamine 4 is a standard microporous cross-
linked polystyrene resin that has been applied several times
as a scavenging reagent for electrophiles,7 supported ethyl-
enediamine 5 belongs to a family of more recently introduced
functionalized silica gel scavengers that are prepared from
high-purity silica gel. In addition to the convenience in
handling (no static charges), these materials have the
advantage that they do not need to swell and therefore can
be used with a variety of solvents.10 We were particularly
interested to compare the quenching capabilities of both
scavengers toward anhydrides under conventional and mi-
crowave conditions in our protocol. For ease of monitoring
by HPLC the acylation with Bz2O was used as a model study.
1. Microwave-Assisted Acylations. Initially, various
acylation conditions involving DHPM 1A as a model
substrate and two representative anhydrides were investigated
(Scheme 1). In general, these acylations are known to occur
Scheme 1
To compare the quenching behavior of the support-bound
scavengers, a number of microwave-assisted acylation runs
of DHPM 1A with Bz2O were performed utilizing the
optimized conditions described above (10 min at 180 °C).
Immediately after cooling to room temperature, 3.0 equiv
(based on the 0.25 mmol starting material, total N loading)
of the nucleophilic amine scavengers were added as solids.
The room-temperature quenching kinetics are displayed in
Figure 1. Complete scavenging (no anhydride detectable by
HPLC) of the remaining, unreacted 1.5 equiv of anhydride
took 1-2 h for the polystyrene-based diamine 4 and 2-4 h
for the silica-based diamine 5. Note that a rather small
number of functional group equivalents for anhydride
sequestration was used in these experiments (ca. 2 equiv
supported amine functionality per excess anhydride molecule,
corresponding to an equimolar amount of diamine units). For
comparison purposes (see below), the hydrolysis rate of Bz2O
achieved by addition of 10 equiv of water is also included
in Figure 1 (ca. 6 h for complete conversion).
regioselectively at the more nucleophilic N3 position, requir-
ing many hours of heating at high temperatures even for
reactive anhydrides such as acetic anhydride.9 After experi-
mentation with a variety of solvents, tertiary bases, and
catalysts, we quickly arrived at conditions where complete
and clean conversion of the model substrate DHPM 1A with
acetic anhydride (Ac2O) could be achieved within 10 min
using microwave flash heating to 130 °C in sealed vessels
(3 bar pressure). These optimized conditions involving 0.25
mmol of starting material utilized 2.5 equiv each of the
anhydride and triethylamine (TEA) as base, 0.2 equiv of
4-(N,N-dimethylamino)pyridine (DMAP) as a catalyst, and
acetonitrile (0.5 mL) as solvent. For the considerably less
reactive benzoic anhydride (Bz2O), a reaction temperature
of 180 °C (10 bar pressure) under otherwise identical
conditions was required in order to achieve almost complete
conversion (1-3% of starting material remaining) within 10
min. In contrast to the aliphatic anhydride, however, here a
significant amount (ca. 12%) of the bis-acylated product 3Ab
Although the scavenging experiments described above
required a considerably longer period as compared to the
microwave-assisted acylation step, we were delighted to
(10) (a) Palmacci, E. R.; Hewitt, M. C.; Seeberger, P. H. Angew. Chem.,
Int. Ed. 2001, 40, 4433-4436. (b) McComas, W.; Chen, L.; Kim, K.
Tetrahedron Lett. 2000, 41, 3573-3576. (c) Thompson, L. A.; Combs, A.
P.; Trainor, G. L.; Wang, Q.; Langlois, T. J.; Kirkland, J. J. Comb. Chem.
High Throughput Screen. 2000, 3, 107-115.
(8) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879-888.
(9) Kappe, C. O. Tetrahedron 1993, 49, 6937-6963 and references
therein.
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Org. Lett., Vol. 5, No. 8, 2003
Dallinger, Doris
