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Alexander Stadler and C. Oliver Kappe*
First Symposium of the European Society For Combinatorial Sciences, Eurocombi-1, July 1-5, 2001, Budapest, Hungary
Institute of Chemistry, Organic and Bioorganic Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austriaemail: [email protected]
Introduction:
(A) Isourea-Method
(B) Anhydride-Method
(1:2)
DCM / DMF0°C, 30 min
PhO
O
Ph
O
+N C NPh
O
HO
O
O
PhP
P OH DMAP (cat.)NMP, 200°C
99 %500 W, 10 min
DCM / DMF 9:1
DMAP (cat.)+N C N
NH
N O
O
PhPhHO
O
O
O
PhP
P OH
NH
O N
O
Ph
58 %
thermodynamicallymore stable
http://www.milestonesci.com
„open vessel“ system
T (°C) Time (PhCO)2O Conversion
10 min10 min
10 min10 min
10 min10 min
5080
120150200200
3 eq3 eq3 eq3 eq3 eq5 eq
27 %39 %48 %53 %74 %99 %
open vessel
T (°C) Time Conversion
15 min15 min15 min15 min
68 (50W)89 (100W)
132 (200W)153 (400W)
48 %73 %53 %50 %
sealed vessel
HO2C
99% (5 min) 98% (10 min)
HO2CMe
93% (10 min)
HO2C Me
98% (3 min)
HO2C
Me87% (15 min)
HO2CMe
Me
95% (10 min)
HO2C
Br92% (15 min)
HO2CCl
Cl99% (5 min)
HO2C
Cl88% (10 min)
HO2CI
95% (10 min)
HO2C
I99% (3 min)
HO2C
Cl
Cl
94% (3 min)
HO2COMe
99% (10 min)
HO2C
OMe
85% (3 min)
HO2C
NO2
97% (10 min)
HO2C NO2
NO2
88% (3 min)
HO2C
NO293% (3 min)
HO2C
CN
73% (10 min)
HO2C
CO2Me
87% (10 min)
HO2C
2a 2b 2c 2d 2e
2i 2j 2k 2l 2m 2n
2o 2p 2q2r 2s
2t 2u
2vSHO2C
92% (10 min)
3a 3b
NHO2C
84% (10 min) 86% (10 min)
NHO2C
3c
HO2C
99% (10 min)
4aHO2C
Me
91% (10 min)
4b 4c
88% (10 min)
HO2CMe
4d
89% (10 min)
HO2CCl
4e
87% (10 min)
HO2C
OMe
4f
93% (10 min)
HO2C
OMe
HO2C
84% (10 min)
HO2C C5H11
74% (10 min)
4g 4h
2g2f
HO2CBr
88% (10 min)
HO2CCl
95% (15 min)
98% (10 min)
HO2C Br
2h
NMP, 700 W, 5-10 min
Cs2CO3 (2.0 eq) O
O
ArP
(Merrifield)
PC l
Ar-CO2H (1.5 eq)
Esterification of Polymer-Supported Alcohol
Acknowledgement: This work was supported by the Austrian Science Fund (FWF, Project P-11994-CHE)
Microwave Equipment
Acid Attachment to Merrifield Resin (NMP, 200°C)
PTFA/DCM = 1:1
500 W, 30 min>99%
120°C, 7 bar
OO
O
PhP h
O
H
(Merrifield)
Our experiments have shown that efficient attachment of carboxylic acids to chloromethylated
polystyrene support is achieved by microwave flash heating in N-methylpyrrolidone (NMP)
within 5-10 min.
Employing microwave irradiation, acidolysis of the Merrifield linker can furthermore be carried
out quantitatively using a conventional TFA/DCM mixture under elevated pressure.
Stadler A., Kappe C.O., Eur. J. Org. Chem., 2001, 919-925
The Effect Of Microwave Irradiation Towards Carbodiimide-Mediated Esterifications On Solid Phase
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.
Milestone MLS 1600 Multimode Batch Reactor
Based on earlier results, esterification of Wang resin should also be achieved more
rapidly by microwave irradiation, following the standard protocols. However, during
the isourea-method, rearrangement of the thermolabile intermediate into the
thermodynamically stable N-acylurea is observed.
On the other hand significant rate enhancements were observed for the coupling of
benzoic anhydride derivatives to polystyrene-supported alcohol using microwave
flash heating in NMP. Reaction times were reduced from 2-3 days to 10 min by
microwave dielectric heating.
Stadler A., Kappe C.O., Tetrahedron, 2001, 3915-3920
Institutfür Chemie
GrazGrazMicrowave & Combichem
shielded thermocouple
