ORGANIC
LETTERS
2000
Vol. 2, No. 19
2999-3001
Impurity Annihilation:
Chromatography-Free Parallel Mitsunobu
Reactions
Anthony G. M. Barrett,* Richard S. Roberts, and Ju1rgen Schro1der
Department of Chemistry, Imperial College of Science, Technology and Medicine,
London SW7 2AY, United Kingdom
Received July 10, 2000
ABSTRACT
Mitsunobu reaction of an alcohol ROH with a carboxylic acid, phthalimide, or N-hydroxyphthalimide (NuH) using DNAD (4) and
(diphenylphosphino)polystyrene (11) gave the products RNu. Ring-opening metathetic polymerization of the side product DNADH (3) using
2
Cl2(Cy3P)2RudCHPh (13) and filtration, to remove poly(DNADH ), (diphenylphosphino)polystyrene 11, its oxide, and its adduct with excess
2
DNAD, gave RNu (43−100%, 86−96% purity) without recourse to chromatography.
Over the past few years combinatorial chemistry has
enhanced the synthesis and discovery of pharmaceuticals,
agrochemicals, catalysts, and other fine chemicals. Usually,
parallel or combinatorial reactions are conducted on solid
supports; however, solution-phase parallel synthesis, where
reactions are easier to monitor and analyze, is becoming
increasingly important. The removal of excess reagents or
side products in a solution-phase reaction, however, can often
be problematic, especially with an automated production of
libraries of compounds. Some useful methods have already
been developed, including automated chromatographic tech-
niques, fluorous-phase chemistry,1 polymer-supported re-
agents,2 and scavenger chemistry.3
simple filtration as an insoluble product. This strategy was
successfully applied to the synthesis of amides and sulfona-
mides. The excess of an acyl or sulfonyl chloride or of an
amine reagent was removed by formation of an insoluble,
highly cross-linked polymer by reaction with 1,4-benzene-
diisocyanate and pentaethylenehexamine. To extend the
strategy, we investigated the use of a ruthenium alkylidene
catalyzed ring-opening metathetic (ROM) polymerization5
for the annihilation of the azodicarboxylate ester and/or the
triarylphosphine reagents used in a Mitsunobu reaction.6 In
this venture we sought to use the Grubbs catalyst 13, since
it is known to tolerate diverse functionality, thereby making
it ideal for the impurity annihilation protocol. In principle
Recently, we reported a new strategy for solution-phase
combinatorial chemistry, “impurity annihilation”.4 The ap-
proach is based upon the selective derivatization by polym-
erization of all contaminants, which are then removed by
(3) (a) Kaldor, S. W.; Siegel, M. G.; Fritz, J. E.; Dressman, B. A.; Hanh,
P. J. Tetrahedron Lett. 1996, 37, 7193. (b) Coppola, G. M. Tetrahedron
Lett. 1998, 39, 8233. (c) Pascual-Alfonso, E.; Avendan˜o, C. Mene´ndez, J.
C. Synlett 2000, 205.
(4) Barrett, A. G. M.; Smith, M. L.; Ze´cri, F. J. Chem. Commun. 1998,
2317.
(5) (a) Gibson, V. C. AdV. Mater. 1994, 6, 37. (b) Grubbs, R. H.; Miller,
S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446. (c) Schrock, R. R.; Murdzek,
J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O’Regan, M. J. Am. Chem.
Soc. 1990, 112, 3875.
(6) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 2380.
(b) Mitsunobu, O. Synthesis 1981, 1. (c) Hughes, D. L. Org. React. 1992,
42, 335.
(1) (a) Curran, D. P.; Hadida, S. J. Am. Chem. Soc. 1996, 118, 2531. (b)
Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1174. (c) Curran, D. P.;
Hadida, S.; Kim, S. Y. Tetrahedron 1999, 55, 8997. (d) Linclau, B.; Sing,
A. K.; Curran, D. P. J. Org. Chem. 1999, 64, 2835.
(2) (a) Caldarelli, M.; Habermann, J.; Ley, S. V. J. Chem. Soc., Perkin
Trans. 1 1999, 107. (b) Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.;
Ze´cri, F. J. Org. Lett. 1999, 1, 579. (c) Barrett, A. G. M.; Cramp, S. M.;
Roberts, R. S.; Ze´cri, F. J. Org. Lett. 2000, 2, 261.
10.1021/ol006313g CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/25/2000