4th International Microwaves in Chemistry Conference, March 8-11, 2006, Orlando, Florida

Interfacing Microwave Synthesis with Enabling

Technologies in Drug Discovery

Doris Dallinger and C. Oliver Kappe*

Institute of Chemistry, Organic and Bioorganic Chemistry, Karl-Franzens University Graz, Heinrichstrasse 28, A-8010-Graz, Austria
email: do.dallinger@uni-graz.at website: http://www.maos.net

Introduction

Modern drug discovery steadily relies on high-speed organic synthesis and combinatorial chemistry techniques for the rapid generation of compound
libraries. Microwave-assisted organic synthesis in combination with polymer-assisted solution phase (PASP) methods are powerful techniques that are
frequently applied in both academia and industry.
Here we report on the rapid synthesis/decoration of privileged heterocyclic scaffolds, namely the dihydropyrimidine (DHPM) scaffold, by applying
microwave heating in conjunction with PASP approaches. The use of resin-bound catalysts, reagents and scavengers as well as fluorous reagents in
conjunction with microwave heating will be described for amidations, esterifications via a Mitsunobu protocol [1] and N-acylations [2].

[1] Desai, B.; Dallinger, D.; Kappe, C. O. Tetrahedron 2006, 62, in press.
[2] Dallinger, D.; Gorobets, N. Yu.; Kappe, C. O. Org. Lett. 2003, 5, 1205. Dallinger, D.; Gorobets, N. Yu.; Kappe, C. O. Mol. Diversity 2003, 7, 229.

 Polymer-supported catalysts  Polymer-supported reagents

Acylation is used for a protection purpose at the N3-position of the DHPM. For ease of Polymer-bound carbodiimide with subsequent SPE purification is used in this amidation
purification, polymer-bound DMAP is used as acylation catalyst. protocol at the DHPM-C-5 position.

N O N
C
N N
Z PS-Wang Z
Ph MeCN/THF Ph O O O
HOBt, DMA
EtO2C H MW, 130 °C, 15 min EtO 2C R5
N N Me
MW, 100-120 °C, 15 min
HO NH N NH
+ Ac2O + NH2R 5 H
Me N O EtOH/HCl Me N O R6 N X R6 N X
MW, 130 °C, 15 min
H H 1 then SPE 1
R R
(Si-carbonate)


11 examples 10 examples

Polymer-supported scavengers
R1, R6 = H, alkyl
37-89 % yield
R5 = benzyl, n-Pr
X = O, S
Z = Cl, Br, NO2, Me

In order to synthesize a library of N3-acylated DHPMs, we employed this high-throughput

protocol which includes a scavenging step to remove both excess anhydride and bis-acylated
byproduct.
 Fluorous reagents
Scavenger

MW, 100 °C, 5 min

To overcome the laborious purification of the Mitsunobu reaction, we decided on a fluorous
approach using fluorous Mitsunobu reagents for the esterification at the DHPM-C-5
R4 3
R4 R4
position.
(R CO)2O, TEA, DMAP O O
E H MeCN E E 3
N N R3 N R
MW, 100-180°C, 5-20 min
R6 N X R6 N X R6 N X O Ph O Ph
1. F-TPP, F-DIAD, THF
R1 R1
MW, 110 °C, 10-30 min
5
R3 = aryl, alkyl O R3 R
HO NH O NH
R1, R6 = H, alkyl R5-OH
with (R 3CO)2O: for R 1 = H 2. F-NCO (scavenging)
R4 = alkyl, aryl bas Al2O3/K2CO 3 (2:1)
activated carbon SPE 10-15% yield
Me N O
MW, 110 °C, 30 min
Me N O
E = ester, acyl, amide SiO 2 R1 R1
X = O, S 3. F-SPE (purification)

R1 = H, Me R5 = prim. + sec. alkyl, 5 examples

28 member library cyclic 30-69 % yield
32-99 % isolated yield
81-99 % purity
O O
C 8F 17(CH 2)2 PPh 2
C6F13 O N N O C 6F 13

 Several scavenging reagents A were evaluated both under rt and

F-TPP F-DIAD
NCO
MW (80-100 °C) conditions (see data B and C ):
C8F17 F-NCO

A • Polystyrene-bound ethylenediamine
 Conclusion
• Functionalized silica gel ethylenediamine

• StratoSpheres Plugs (diethylenetriaminomethyl) The combination of MW heating with PASP methods is a powerful tool for organic
synthesis. Not only an acceleration of reactions is possible but also the
• SynPhase Lanterns (aminomethyl)
purification issue is simplified. Here we showed examples for the use of polymer-
bound catalysts, scavengers and reagents as well as fluorous reagents to ease

Room Temperature (25 °C) Microwave Heating (80-100 °C) the sometimes laborious reaction work-up.

B C
100
100
Acknowledgements
80
80
60 This work was supported by the Austrian Science Fund (FWF, I18-N07).
% B z2 O

60
% Bz2 O

40
40 d We thank Biotage (Uppsala, Sweden) for the use of the Emrys Synthesizer and
c
Initiator Eight. We also thank Silicycle Inc., Mimotopes and Polymer Laboratories
20
d 20
c b
0
Ltd. for providing the scavengers used in this study and FTI for the fluorous
b 0
a a
0
0

150 300
5
10
30
60
10 5

450
1 20
1 80

600
24 0

Mitsunobu reagents.
3 00
36 0
4 20
48 0

t [min] time [sec]