ROMPGEL Scavengers: A high-loading supported anhydride for sequestering amines and hydrazines

Article abstract of DOI:10.1021/ol006191s

(formula presented) A versatile method for sequestering excess amines and hydrazines is reported using a high-loading ROMPGEL anhydride polymer.

Full text of DOI:10.1021/ol006191s

ORGANIC
LETTERS
2000
Vol. 2, No. 17
2663-2666
ROMPGEL Scavengers: A High-Loading
Supported Anhydride for Sequestering
Amines and Hydrazines
,†
Thomas Arnauld,† Anthony G. M. Barrett,* Susan M. Cramp,‡
Richard S. Roberts,† and Frederic J. Ze´cri†
Department of Chemistry, Imperial College of Science, Technology and Medicine,
London, SW7 2AY, United Kingdom, and AVentis CropScience, Fyfield Road,
Ongar, Essex, CM5 0HW, United Kingdom
agmb@ic.ac.uk
Received June 12, 2000
ABSTRACT
A versatile method for sequestering excess amines and hydrazines is reported using a high-loading ROMPGEL anhydride polymer.
Combinatorial chemistry has emerged as a powerful adjunct
to drug discovery and catalyst and material development and
optimization.1 During the past decade, interest in methodolo-
gies for efficient parallel solution-phase synthesis has
emerged. Such methods are appropriate for the preparation
of large and diverse libraries yet with simplified analysis
and usually shorter development times compared with
synthesis on insoluble polymer resin supports. The purifica-
tion and isolation of target compounds, however, remains a
significant problem for solution-phase methodology.2 Among
the diverse techniques developed, the use of scavenger
reagents plays an important role in this regard.3
Scavengers are usually functionalized insoluble resins
which react selectively with excess reagents or side products
in a crude reaction mixture, leaving the desired product of
enhanced purity remaining in solution. Since the pioneering
work of Kaldor and co-workers4 with polystyrene isocyanate
resin (used to scavenge excess amine reactants in the
formation of amides), a variety of new polystyrene-supported
electrophiles including acid chlorides,4 isothiocyanates,5 and
aldehydes6 have emerged. These resins are usually synthe-
sized from Merrifield resin, and as such the issues of resin
loading, swelling, and site accessibility come into play.
Several strategies to overcome the low loading of poly-
styrene have been reported: the use of a higher loading
Merrifield resin substituted by isatoic anhydride gave a
† Imperial College of Science, Technology and Medicine.
‡ Aventis CropScience.
(1) (a) Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.;
Gordon, E. M. J. Med. Chem. 1994, 37, 1233. (b) Gordon, E. M.; Barrett,
R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994,
37, 1385. (c) Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C.
Tetrahedron 1996, 52, 4527. (d) Hermkens, P. H. H.; Ottenheijm, H. C. J.;
Rees, D. C. Tetrahedron 1997, 53, 5643. (e) Booth, S.; Hermkens, P. H.
H.; Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron 1998, 54, 15385.
(2) (a) Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1174-1196. (b)
Flynn, D. L.; Crich, J. Z.; Devraj, R. V.; Hockerman, S. L.; Parlow, J. J.;
South, M. S.; Woodard, S. Curr. Opin. Chem. Biol. 1999, 3, 320. (c) Bunin,
B. A. The Combinatorial Index; Academic press: San Diego, CA, 1998.
(d) Booth, R. J.; Hodges, J. C. Acc. Chem. Res. 1999, 32, 18.
(3) (a) Flynn, D. L.; Crich, J. Z.; Devraj, R. V.; Hockerman, S. L.; Parlow,
J. J.; South, M. S.; Woodard, S. J. Am. Chem. Soc. 1997, 119, 4874. (b)
Booth, R. J.; Hodges, J. C. J. Am. Chem. Soc. 1997, 119, 4882.
(4) Kaldor, S. W.; Siegel, M. G.; Fritz, J. E.; Dressman, B. A.; Hanh, P.
J. Tetrahedron Lett. 1996, 37, 7193.
(5) The Combinatorial Chemistry Catalog, March, 1999; Novabiochem
Corp.; pp 1-3, S63, S66-7
(6) Creswell, M. W.; Bolton, G. L.; Hodges, J. C.; Meppen, M.
Tetrahedron 1998, 39, 1121.
10.1021/ol006191s CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/25/2000

scavenger for amines (anhydride loading 3.2 mmol g-1).7
Suspension copolymerization of (methacryloyloxy)ethyl iso-
cyanate with 10% divinylbenzene gave an isocyanate resin
(isocyanate loading 5.2 mmol g-1).8 Alternatively, radical
copolymerization of 3-isopropenyl R,R-dimethylbenzyl iso-
cyanate with styrene initiated by a TEMPO-functionalized
Merrifield resin generated graft copolymer spheres, known
as “Rasta” beads (isocyanate loading 2.5 mmol g-1).9
In addition to the scavenger resins, ion-exchange tech-
niques have been used for the removal of amine contaminants
from nonbasic product. The amine is either removed from
solution using a supported acid resin10 or is first function-
alized prior to removal of the derivative by a scavenger
resinsa technique known as “tagging”. Solution-phase
reaction of an amine contaminant with tetrafluorosuccinic
anhydride and subsequent sequestration with basic resins was
described by Flynn and Parlow to purify amides.11 Polysty-
renesulfonic acid resins have also been reported as amine
scavengers.12
enger. Finally the loading of the ROMPGEL scavenger is
high because all the monomers are substituted with the
desired functionality and hence there is absence of redundant
polymer backbone architecture. Moreover, only a small
excess of ROMPGEL is required because of the excellent
site accessibility and fast scavenging.
ROM polymerization of commercially available anhydride
1 using Cl2(PCy3)2RudCHPh14 has already been reported
by both Grubbs15 and Buchmeiser,16 the latter group reporting
the affinity between the diacid ROMP derived from 1 by
hydrolysis with amines and metal ions.
In our hands, co-ROM polymerization of anhydride 1 with
norbornadiene (20 mol %) using the Grubbs catalyst
Cl2(PCy3)2RudCHPh gave a white solid, insoluble in most
organic solvents, and with an anhydride loading of 5.4 mmol
g-1 (Scheme 1).
Scheme 1. Synthesis of ROMPGEL Anhydride Scavenger
Herein we report the use of a ring-opening metathesis
(ROM) polymer-supported anhydride as a selective high-
loading scavenger for amines and hydrazines (we term these
polymers “ROMPGELs”). This work is an extension of other
recent applications of ROMPGEL reagents for solution-phase
parallel synthesis.13
The requirements for a good amine scavenger include
effectiveness over a broad range of nucleophilicity (especially
toward amines such as anilines), good purity of the products
obtained, efficiency (in terms of reaction time), simplicity
of the experimental procedure, and especially high loading.
Factors such as cost and availability are also important. Most
available scavengers are based on a polystyrene support and,
although efficient, are frequently slow for complete seques-
tration. Modest loadings mean that a substantial quantity of
resin is required which can prove expensive and volume
inefficient, especially once the resin is swollen. Moreover,
variation in the quality of the libraries produced has also
been noted with different resin batches.
We believe that ROMPGELs have all the qualities and
advantages necessary to fulfill the requirements for superior
scavengers. First, substituted norbornene and 7-oxanor-
bornene monomers are readily available (from cyclopenta-
diene and furan respectively) and inexpensive. Second, all
transformations to attach the desired functionality are carried
out on the monomer, which is then polymerized in high yield.
This is a marked contrast to the synthesis of polystyrene-
based scavengers and greatly simplifies the synthesis,
authentication and quality control of the ROMPGEL scav-
To our delight, a slight excess of ROMPGEL 2 (1.5 equiv)
rapidly scavenged amines from solution. Additionally, the
carboxylic acid function released upon opening the anhydride
could also scavenge amines from solution; hence the two
functionalities account for a total scavenging potential of 10.8
mmol g-1. Moreover, no byproducts were generated during
the scavenging process (Scheme 2).
Scheme 2. Sequestration of Excess Amine
(7) Coppola, G. M. Tetrahedron Lett. 1998, 39, 8233.
(8) Zhu, D. W. Macromolecules 1996, 29, 2813.
(9) Hodges, J. C.; Harikrishnan, L. S.; Ault-Justus, S. J. Comb. Chem.
2000, 2, 80.
(10) (a) Shuker, A. J.; Siegel, M. G.; Matthews, D. P.; Weigel, L. O.
Tetrahedron Lett. 1997, 38, 6149. (b) Laurence, R. M.; Biller, S. A.;
Frysman, O. M.; Poss, M. A. Synthesis 1997, 553.
(11) (a) Parlow, J. J.; Mischke, D. A.; Woodard, S. S. J. Org. Chem.
1997, 62, 5908. (b) Parlow, J. J.; Naing, W.; South, M. S.; Flynn, D. L.
Tetrahedron Lett. 1997, 38, 7959. (c) Parlow, J. J.; Flynn, D. L. Tetrahedron
1998, 54, 4013.
(12) Siegel, M. G.; Hahn, P. J.; Dressman, B. A.; Fritz, J. E.; Grunwell,
J. R.; Kaldor, S. W. Tetrahedron Lett. 1997, 38, 3357.
Ureas, thioureas, amides, sulfonamides, carbamates, imi-
nes, and hydrazones were synthesized in excellent yields and
2664
Org. Lett., Vol. 2, No. 17, 2000

purities by reaction between an excess of amine or hydrazine
(3 equiv) with the corresponding isocyanate, isothiocyanate,
acid chloride or arenesulfonyl chloride, chloroformate, or
aldehyde, respectively (see Table 1). Subsequent removal
the reaction, 1.5 equiv of ROMPGEL 2 (based on the loading
of 10.8 mmol g-1) per equivalent of excess amine was needed
to cleanly afford the desired product (compounds A-C,
F-H, T-W, and Y). Surprisingly, even when the nucleo-
phile possessed a second tertiary amine (compounds D and
E) or a basic moiety (compound X), the corresponding amino
ureas or hydrazones, which could in theory also be scavenged
as an ammonium salt, were isolated in excellent yields and
purities using 3 equiv of ROMPGEL 2. Presumably the
excess diamine is scavenged as amine salt 5, thereby tying
up the carboxylic acid functionality (Scheme 3).
Table 1. Scavenging Results
Scheme 3. Sequestring of Diamino Reagent
Amides, sulfonamides, and carbamates (compounds I-S)
were prepared in excellent yields and purities by reaction of
excess amines with acyl or arenesulfonyl chlorides or
chloroformates. In these cases, polyvinylpyridine was added
to the reaction mixture to scavenge hydrogen chloride. Three
equivalents of scavenger 2 per equivalent of excess amine
were used to trap the unreacted amine. The larger amount
was required due to the formation of hydrogen chloride and
the necessity to avoid formation of the ammonium salt in
the solution phase. Presumably the yield of amide J was low
under the standard reaction conditions due to poor conversion
as a result of steric congestion.
As an alternative to polyvinylpyridine, ROMPGEL-sup-
ported morpholine reagent 8 could be used instead. The novel
scavenger 8 was readily synthesized from exo-C-arylation
of norbornadiene18 using iodide 6 and subsequent ROM
polymerization of 7 (Scheme 4). Compound M was isolated
a All the reactions were carried out with 3 equiv of the nucleophile
relative to the electrophile. Parentheses refer to the isolated yield and the
number of equivalents of anhydride scavenger 2 used (10.8 mmol g-1
loading) relative to the excess amine. All the products have been
characterized by 1H NMR, 13C NMR, GC/MS (one peak), IR, and HRMS.
The superscripts 1-5 refer to the following: 1, product was mostly insoluble
in CH2Cl2; 2, overnight, room temperature for the scavenging step; 3,
ROMPGEL-supported morpholine 8 was used instead of polyvinylpyridine;
4, the hydrochloride salt of the amino ester was used; 5, Et2O was used
instead of CH2Cl2 and 4 Å molecular sieves were added to the mixture.
of the excess nucleophile was performed using the ROMP-
GEL scavenger 2.17
In the case of formation of urea, thiourea, imine, and
hydrazone where no hydrogen chloride was produced during
Scheme 4. Synthesis of ROMPGEL -Supported Morpholine
(13) (a) For ROMPGEL Horner-Emmons reagent, see: Barrett, A. G.
M.; Cramp, S. M.; Roberts, R. S.; Ze´cri, F. J. Org. Lett. 1999, 1, 579. (b)
For ROMPGEL acylation reagent, see: Barrett, A. G. M.; Cramp, S. M.;
Roberts, R. S.; Ze´cri, F. J. Org. Lett. 2000, 2, 261. (c) For ROMPGEL
synthesis of 1,2,4-oxadiazoles, see: Barrett, A. G. M.; Cramp, S. M.;
Roberts, R. S.; Ze´cri, F. J. Comb. Chem. High Throughput Screening 2000,
3, 131.
(14) Catalyst is commercially available from Fluka. Schwab, P.; France,
M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1995, 34,
2039.
(15) Kanaoka, S.; Grubbs, R. H. Macromolecules 1995, 28, 4707.
(16) Buchmeiser, M. R.; Atzl, N.; Bonn, G. K. J. Am. Chem. Soc. 1997,
119, 9166.
(17) Typical procedure: To a solution of isocyanate (0.25 mmol) in
methylene chloride (3 mL) was added the amine (0.75 mmol). The solution
was stirred at room temperature for 3 h before addition of 70 mg of
ROMPGEL scavenger 2 (0.75 mmol). The suspension was stirred at room
temperature for 3 h, filtered off, and washed with methylene chloride (2 ×
3 mL). The solvent was then removed in a stream of nitrogen to give the
desired urea.
Org. Lett., Vol. 2, No. 17, 2000
2665

in 98% yield and excellent purity (>95% by 1H NMR) using
1.5 equiv of ROMPGEL morpholine 8 instead of polyvi-
nylpyridine.
hydrazines. This readily available ROMPGEL polymer has
demonstrated considerable potential in the sequestration of
excess of amines and hydrazines. Excellent isolated yields
and purities of ureas, thioureas, amides, sulfonamides,
carbamates, imines, and hydrazones were obtained. Further
applications of ROMPGEL will be reported in due course.
Amine salts (e.g., valine methyl ester hydrochloride) could
also be used to prepare amides (compound N), and in this
case polystyrene-supported guanidine (P-TBD)19 was used
as a proton scavenger with triethylamine as a proton shuttle.
The poorly reactive 3,5-dimethoxyaniline (compound K) was
successfully removed from the reaction mixture upon a
longer (overnight) exposure to ROMPGEL scavenger 2 and
gave the desired amide in 90% yield and good purity (>95%
Acknowledgment. We thank Aventis CropScience for
their generous support of this project (F.J.Z.), Rhoˆne-Poulenc
Rorer, under the auspices of the TeknoMed project (R.S.R.),
GlaxoWellcome Ltd. for their endowment (A.G.M.B.) and
postdoctoral fellowship (T.A.), and the Wolfson Foundation
for establishing the Wolfson Centre for Organic Chemistry
in Medical Science at Imperial College.
1
by H NMR). The reaction of amino alcohol (compound I)
demonstrated the selectivity of the scavenger toward amines
in the presence of alcohols. No significant loss of product
was detected using the standard scavenging conditions.
In summary, we have developed the use of a high-loading
ROMPGEL-supported anhydride scavenger for amines and
Supporting Information Available: General procedures
for the synthesis and applications of ROMPGELs 2 are
provided as well as representative spectra of compound L
obtained by the ROMPGEL strategy. This material is
available free of charge via the Internet at http://pubs.acs.org.
(18) Arcadi, A.; Marinelli, F.; Bernocchi, E.; Cacchi, S.; Ortar, G. J.
Organomet. Chem. 1989, 368, 249.
(19) Xu, W.; Mohan, R.; Morrissey, M. M. Tetrahedron Lett. 1997, 38,
7337.
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