Transcript The Effects of Microwave Irradiation Towards Carbodiimide

The 12th European Symposium on Organic Chemistry (ESOC-12), July 13-18, 2001, Groningen, The Netherlands
Institut
für Chemie
Microwave-Assisted Combinatorial Chemistry.
Examples of High-Speed Solid-Phase Organic Synthesis
Graz
Microwave
& Combichem
C. Oliver Kappe,* Alexander Stadler, Gernot A. Strohmeier
Institute of Chemistry, Organic and Bioorganic Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria
email: [email protected]
Introduction:
One of the most common solid-phase reactions in combinatorial synthesis involves the coupling of an acid (i.e. an amino acid) to polystyrene solid supports (i.e. Wang or Merrifield resin). A
number of publications have reported the coupling of carboxylic acids to Merrifield resin via the cesium salt method and the esterification of Wang resin using carbodiimide either via the
isourea method or the symmetrical anhydride method. Since the reaction times using conventional conditions have been reported to be rather long (16-48 h) we have investigated the
effects of microwave irradiation towards both of these reactions using benzoic acid derivatives.


Microwave Equipment
Milestone MLS 1600
Multimode Batch Reactor
Esterification of Polymer-Supported Alcohol
(A) Isourea-Method
+
N C N
„open vessel“ system
N
DMAP (cat.)
O
DCM / DMF 9:1
N
Ph
HO
H
O
O
Ph
O
Ar-CO2H (1.5 eq)
Cl
O
Cs2CO3 (2.0 eq)
P
Ar
P
H
N
NMP, 700 W, 5-10 min
O
(Merrifield)
O
N
Ph
O

Ph
T (°C)
68 (50W)
89 (100W)
132 (200W)
153 (400W)
58 %
thermodynamically
more stable
http://www.milestonesci.com
sealed vessel
O
P
shielded thermocouple
OH
P
Time
Conversion
15 min
15 min
15 min
15 min
48 %
73 %
53 %
50 %
(B) Anhydride-Method
Acid Attachment to Merrifield Resin (NMP, 200°C)
O
N C N
Me
Me
HO2C
HO2C
HO2C
2a
2b
2c
99% (5 min)
98% (10 min)
HO2C
Me HO2C
2d
93% (10 min)
2e
Me Me
98% (3 min)
87% (15 min)
Br
2h
HO2C
HO2C
2f
2g
95% (15 min)
HO2C
HO2C
HO2C
HO2C
2i
2j
2k
2l
2m
2n
98% (10 min)
Cl
99% (5 min)
OMe
HO2C
HO2C
2o
2p
HO2C
94% (3 min)
Cl
Ph
HO2C
2v
3a
87% (10 min)
HO2C
S
HO2C
N
3b
92% (10 min)
N
3c
84% (10 min)
4a
86% (10 min)
OMe
HO2C
Cl
4d
89% (10 min)
HO2C
HO2C
4e
4f
87% (10 min)
HO2C
CN
HO2C
HO2C
4g
4h
NMP, 200°C
DMAP (cat.)
O
2u
CO2Me
73% (10 min)
93% (3 min)
HO2C
HO2C
4b
4c
99% (10 min)
Ph
O
HO2C
P
Me
HO2C
OH
P
2t
NO2
88% (3 min)
O
Cl
99% (3 min)
HO2C
NO2
97% (10 min)
O
NO2
2s
2r
2q
OMe
NO2
99% (10 min)
85% (3 min)
88% (10 min)
HO2C
HO2C
I
95% (10 min)
open vessel
DCM / DMF
0°C, 30 min
88% (10 min)
HO2C
Cl
92% (15 min)
91% (10 min)
Ph
(1:2)
HO2C
Br
95% (10 min)
HO
Br
I
Cl
HO2C
Cl
+
O
T (°C)
Time
50
80
120
150
200
200
10 min
10 min
10 min
10 min
10 min
10 min
(PhCO)2O Conversion
3 eq
3 eq
3 eq
3 eq
3 eq
5 eq
27 %
39 %
48 %
53 %
74 %
99 %
Ph
99 %
500 W, 10 min
Me
88% (10 min)
Stadler A., Kappe C.O., Tetrahedron, 2001, 3915-3920
C5H11
OMe
93% (10 min)
74% (10 min)
84% (10 min)

Conclusion
Employing microwave irradiation, acidolysis of the Merrifield linker can furthermore be carried
out quantitatively using a conventional TFA/DCM mixture under elevated pressure.
O
P
O
(Merrifield)
 Esterifications to solid support in 3-15 min instead of
O
Ph
TFA/DCM = 1:1
Ph
HO
500 W, 30 min
120°C, 7 bar
>99%
Stadler A., Kappe C.O., Eur. J. Org. Chem., 2001, 919-925
24-72 hours
 Isourea method causes byproduct due to rearrangement
of the thermolabile intermediate
 Significant rate enhancement for coupling of benzoic
anhydride derivatives using microwave flash heating
Acknowledgement:
This work was supported by the Austrian Science Fund (FWF, Project P-11994-CHE)