ULTRAMINE: A high-capacity polyethylene-imine-based polymer and its application as a scavenger resin

Article abstract of DOI:10.1002/chem.200400314

The synthesis of a novel high-loading polyethylene-imine resin (ULTRAMINE) is described, and its application as a scavenger resin in various acylation reactions is demonstrated. The inverse suspension polymerization technique was used for the synthesis of well-defined spherical polymer beads. Polymer beads with different cross-linking densities were synthesized according to the degree of acryloylation of the polyethylene-imine polymer. The resin was characterized by various spectroscopic techniques. The size, shape, and morphological features of the resin were demonstrated by microscopy. The resin showed excellent swelling properties in both polar and nonpolar solvents. The chemical stability of the resin in various reagents and solvents was investigated and monitored by IR spectroscopy. The mechanical stability of the beads was determined by a single-bead compressive experiment. The ULTRAMINE beads can be used as an excellent scavenger for excess acylating reagent, as demonstrated for a variety of reactions. UL-TRAMINE-red resin was derived from ULTRAMINE through exhaustive reduction of the amide carbonyl groups to yield an all-amine resin.

Full text of DOI:10.1002/chem.200400314

FULL PAPER
ULTRAMINE: A High-Capacity Polyethylene–Imine-Based Polymerand Its
Application as a ScavengerResin
Michael Roice,[a, b] Søren F. Christensen,[b] and Morten Meldal*[a]
Abstract: The synthesis of a novel
high-loading polyethylene–imine resin
(ULTRAMINE) is described, and its
application as a scavenger resin in vari-
ous acylation reactions is demonstrat-
ed. The inverse suspension polymeriza-
tion technique was used for the synthe-
sis of well-defined spherical polymer
beads. Polymer beads with different
cross-linking densities were synthesized
according to the degree of acryloyla-
tion of the polyethylene–imine poly-
mer. The resin was characterized by
various spectroscopic techniques. The
size, shape, and morphological features
of the resin were demonstrated by mi-
croscopy. The resin showed excellent
swelling properties in both polar and
nonpolar solvents. The chemical stabili-
ty of the resin in various reagents and
solvents was investigated and moni-
tored by IR spectroscopy. The mechan-
ical stability of the beads was deter-
mined by a single-bead compressive ex-
periment. The ULTRAMINE beads
can be used as an excellent scavenger
for excess acylating reagent, as demon-
strated for a variety of reactions. UL-
TRAMINE-red resin was derived from
ULTRAMINE through exhaustive re-
duction of the amide carbonyl groups
to yield an all-amine resin.
Keywords: acylation · parallel syn-
thesis · polymerization · polymers ·
scavenger resins
Introduction
braries, whether on solid support or in solution, is the rapid
purification, isolation, and manipulation of chemical library
members during both the intermediate and final synthetic
steps. Solid-phase technology offers advantages such as ease
of separating the products from the reactants in the reaction
medium, ease of split–mix synthesis, and monitoring of
product formation on single beads by using different spec-
tral techniques. Desirable properties in the resin for the ma-
nipulation of the solid support during organic synthesis are
chemical and mechanical stability, compatibility with various
reagents, and swelling in both hydrophilic and hydrophobic
solvents. Merrifield resin, most often used in synthesis, has
high mechanical stability; however, the swelling in and com-
patibility with various polar reagents and solvents are rather
poor. Furthermore, functionalizations of the resin, for exam-
ple, by chloromethylation, often lead to additional cross-
linking of the polymer.[5] In order to circumvent these prob-
lems, a series of more polar polystyrene-based copolymers
was developed by incorporation of more flexible and polar
moieties into the polymer network. The modified polysty-
rene supports have all been successfully employed for solid-
phase synthesis[6] and include poly(ethylene glycol)–polysty-
rene (PEG-PS),[7] tentagel graft resin,[8] poly(ethylene
glycol) (meth)acrylate cross-linked polystyrene,[9] poly(ethyl-
ene oxide)–polystyrene (PEO-PS),[10] and JandaJelꢀ.[11] The
favorable properties of these resins led to a second genera-
tion of more polar resins including polyamides,[12] poly(ethyl-
ene glycol) polyacrylamide (PEGA),[13] poly(oxyethylene)/
During the last decade solid-phase synthesis has experienced
a renaissance, with exploitation in general organic synthesis
and combinatorial chemistry. Merrifield initially reported
the classical stepwise solid-phase synthesis of peptides exem-
plified by synthesis of a tetrapeptide on divinyl benzene
cross-linked polystyrene resin.[1] Due to the ease of compart-
mentalizing and handling reagents on solid support, cross-
linked polymers have played an important role in the devel-
opment of combinatorial and parallel synthesis.[2] Initially
solid-phase synthesis focused on the preparation of amino
acids or nucleotides, including oligomers of unnatural chem-
ical building blocks, for example, peptoids.[3] The synthesis
of non-oligomeric small-molecule libraries by quantitative
chemical transformations is currently an important research
area.[4] Important for the successful synthesis of chemical li-
[a]Dr. M. Roice, Prof. M. Meldal
Center for Solid Phase Organic Combinatorial Chemistry
Department of Chemistry, Carlsberg Laboratory
Gamle Carlsberg Vej 10, 2500 Valby (Denmark)
Fax : (+45)3327-4708
E-mail: mpm@crc.dk
[b]Dr. M. Roice, Dr. S. F. Christensen
VersaMatrix A/S
Gamle Carlsberg Vej 10, 2500 Valby (Denmark)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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DOI: 10.1002/chem.200400314
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FULL PAPER
poly(oxypropylene) copolymer (POEPOP),[14] superpermea-
ble organic combinatorial chemistry resin (SPOCC),[15]
cross-linked ethoxylate acrylate resin (CLEAR),[16] and glyc-
erol dimethacrylate/polymethylmethacrylate copolymer
(GDMA-PMMA);[17] these resins contain no polystyrene
and present excellent swelling properties both in nonpolar
and in protic and aprotic polar solvents.
Chemistry on solid supports is limited by the problems of
preparative scaling, the difficulty of product validation, and
the inherent decrease of the macromolecular reactivity. So-
lution-phase synthesis has the advantage of scalability, in ad-
dition to easy manipulation and analysis of product. The
major limitation of solution-phase synthesis is in the isola-
tion and purification of the reaction products from the reac-
tion medium, particularly when working with compound
mixtures. The use of polymeric scavenging reagents can
overcome this limitation to a great extent.[18] In scavenging,
the scavenger resins contain active groups that mimic the re-
activity of the limiting reagent in the reaction. After com-
pletion of the reaction, the resin is added to the reaction
mixture to react with excess reagents. Filtering off the resin-
bound reagent provides a relatively pure product in solu-
tion.
None of the above-mentioned polymers meet the require-
ments for an ideal scavenger resin. Their main disadvantage
is the low loading of functional groups for the volume of
resin. The relatively high-capacity polymer poly(vinyl pyri-
dine) (PVP) has been successfully used as a scavenger
resin.[19] Polyethylene–imine-based polymers offer an inher-
ent high amino-group loading and, upon cross-linking, can
be used as scavenger resins. Polyethylene–imine polymers
(for example, Lupasolꢀ) are used in industry for promoting
adhesion between similar and dissimilar materials, to dis-
perse fillers and pigments, to flocculate suspended solids, to
modify surface characteristics, such as charge and hydrophi-
licity, and to scavenge heavy metals and unwanted materi-
als.[20] Polyethylene–imine/aliphatic-polyester copolymers
are used for solubilization and provide a delivery system for
proteins, genes, or drugs.[21] A polyethylene–imine, cross-
linked cellulose sponge and polyethylene–imine polymer
bound on silica gel were used for ion exchange and for chro-
matographic separation of monoclonal antibodies.[22] A poly-
ethylene–imine resin cross-linked with bisaldehyde was re-
cently reported for solid-phase synthesis of peptides.[23] The
polymer formed was granulated and therefore irregular in
shape, which may complicate separation from the product
when used in scavenging. A degradable poly(b-amino ester)
was obtained by conjugate addition of primary and second-
ary amine monomers to diacrylate monomers for use in
gene delivery.[24]
Results and Discussion
Scavenger resins are increasingly important for the separa-
tion of excess reactants and byproducts from solution-phase
chemical reactions. Low cost of synthesis, chemical and me-
chanical stability, high rate of reactant diffusion within the
polymer, and a high density of reactive primary and sec-
ondary amino groups are important properties that deter-
mine the efficacy of an amine scavenger resin. Analogous
with the preparation of poly(ethylene glycol)-based resins, a
novel cross-linked, beaded polymer, ULTRAMINE, based
on polyethylene–imine polymer was designed to provide a
high density of amino groups and appropriate swelling in
both polar and nonpolar solvents. It was obtained by free-
radical inverse suspension polymerization of partially acryl-
oylated polyethylene–imine macromonomers. The chemical,
physical, and mechanical properties of beaded polymers can
be controlled by variation of the degree of polyimine poly-
merization and acryloylation and can be optimized for solid-
phase synthesis or scavenging. The cross-linked polymer
from polymerization of a 15% acryloylated (of all amino
groups) polyethylene–imine macromonomer resulted in
16.5 mmol of amino groups per gram, which is significantly
higher loading than that of previously described scavenger
resins. The radical polymerization of acrylamides is extreme-
ly efficient and was employed in the formation of the UL-
TRAMINE polymer.
Synthesis of monomers: The acylation of amino groups in
polyethylene–imine polymers with different concentrations
of acryloyl chloride formed a series of macromonomers with
various degrees of acrylamide functionality for polymeriza-
tion. The reproducibility of the monomer synthesis and, con-
sequently, the synthesis of polymers with a variable degree
of cross-linking, can be controlled by the use of a well-de-
fined amount of acryloyl chloride in the macromonomer
synthesis. The macromonomers were prepared by the drop-
wise addition of acryloyl chloride to the polyethylene–imine
polymer in dichloromethane at 08C (Table 1; Scheme 1,
Table 1. Yield and loading of functional amines in ULTRAMINE poly-
mers with different cross-linking density and loading after borane reduc-
tion of amides.
Amount[a] of
acryloyl
Acryloylation
Yield of
polymer
Loading
Loading
after red.
ꢀ1
chloride [mL][%][%][mmolg
ꢀ1][mmolg
]
2.4
2.1
1.9
1.6
15.0
13.5
11.5
10.0
>95
91
87
16.5
17.3
17.9
18.6
18.6
19.5
20.4
21.0
80
[a]Added to 7.9 mL polyethylene–imine polymer, Mw =423 gmolꢀ1
.
The present paper describes the development and effi-
cient preparation of a high-capacity, cross-linked, beaded
polyimine resin. As an example of application, the resin was
employed for the scavenging of excess acylating agents in
solution-phase reactions. The resin was prepared by poly-
merization of partially acryloylated polyethylene–imine
macromonomers.
left). The crude reaction mixture consists of polyethylene–
imine chains containing at least one acrylamide functionality
for polymerization.
Polymer synthesis and characterization: To investigate the
polymer synthesis, a bulk polymerization was initially per-
formed. The bulk polymer was ground and passed through a
sieve with a 1 mm mesh. The particles obtained were irregu-
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ULTRAMINE
4407 – 4415
With most commercially avail-
able resins, the structure eluci-
dation of compounds on the
solid support by NMR spectros-
copy is complicated by line
broadening due to inhomogene-
ities and interference by the sig-
nals from the polymer back-
bone. Due to the narrow and
well-defined signals of the UL-
TRAMINE backbone, the resin
may be useful for on-resin
structure elucidation by NMR
spectroscopy. In order to inves-
tigate this, the resin was acylat-
ed with 9-fluorenylmethoxycar-
bonyl (Fmoc) amino benzoic
acid; the MAS NMR spectra of
Scheme 1. Synthesis of ULTRAMINE polymer by inverse suspension polymerization of partially acryloylated
polyethylene–imine polymers. TEMED=N,N,N’,N’-tetramethylethylenediamine.
lar in size and shape (Figure 1a), and the resin was fragile
and shredded small particles when used for scavenging in
chemical reactions.
Spherical polymer beads were then prepared by an in-
verse suspension polymerization method (Scheme 1). The
polymer was synthesized with various cross-linking densities.
The average size and shape of the beads depended on fac-
tors such as suspension medium, amount of surfactant,
amount of initiator, and stirring speed. For the beading of
the ULTRAMINE polymer, three different continuous
phases, n-heptane, n-heptane/CCl4 (6:4), and isopar M (a
mixture of C10–12 hydrocarbons), were tested. The results re-
vealed that the relative density of the suspension medium
has an influence on the size and shape of the polymer bead.
A low-density suspension medium, n-heptane, gave well-de-
fined polymer beads with an even size distribution. The sus-
pended macromonomer mixture has a tendency to precipi-
tate, due to its higher density; this results in improved
mixing with stirring. Sorbitan monolaurate was used as a
suspension stabilizer, ammonium persulphate was the free-
radical initiator, and N,N,N’,N’-tetramethylethylenediamine
(TEMED) was used to promote the reaction. The resin was
suspended in 10% diisopropylethylamine (DIPEA) in
EtOH in order to neutralize the HCl trapped in the resin
during the acryloylation reaction of the macromonomer syn-
thesis. Microscopy of the polymer showed that uniform
spherical beads with less than 1% agglomerates were
formed (Figure 1b and c).
The ULTRAMINE polymer was characterized by IR and
MAS NMR spectroscopy. The IR spectrum shows a sharp
band at 1622 cmꢀ1 corresponding to the amide carbonyl
group and broad bands at 3272 (NH stretch) and 2937 cmꢀ1
1
(CH stretch). The gel-phase H MAS NMR spectrum of the
polymer contained an intense peak at d=3.19 ppm, which
corresponds to the methylene protons of the polymer back-
bone. Peaks at d=3.41, 2.91, and 2.72 ppm correspond to
the amine protons, the a-methylene protons of primary
amino groups, and the CH proton at the cross-linking site,
respectively (Figure S1a in the Supporting Information).
Figure 1. Microscopy of crude ULTRAMINE prepared by a) bulk poly-
merization, b) inverse suspension polymerization (before sieving), and
c) inverse suspension polymerization (after sieving).
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M. Meldal et al.
FULL PAPER
the product contained relatively sharp coupled signals corre-
sponding to the Fmoc group, without interference from the
polymer backbone signals (Figure S1b in the Supporting In-
formation), while the signals of the Abz group close to the
resin were significantly broader probably due to inhomoge-
neity of solvation caused by the high loading.
mined by a compressive stress experiment. The compressive
property is a measure of the behavior of the bead when it is
subjected to compressive stress. The bead (300–500 mm) was
placed between a ccd camera lens and a cylindrical probe,
connected to a strain gauge to measure the force applied,
and an actuator; the sample was then compressed at a con-
stant rate of 10 mmminꢀ1. The camera recorded the defor-
mation of the bead. An apparent compressive modulus (EA)
can then be calculated as the ratio of the apparent compres-
sive stress (sA, the force per area of cross section of the
bead) over the apparent compressive strain (gA, the ratio of
the diameter over the initial diameter). The apparent linear
compressive modulus, EA0 is then given by Equation (1).
Swelling and stability studies of ULTRAMINE: The extent
of swelling determines the access of reagents to active sites
within the polymer network.[25] Swelling in different solvents
is important for the performance of the resins in solid-phase
synthesis, in supported catalysis, as supported reagents, and
as scavengers. The swelling ratio was determined from the
increase in volume of the resin upon incubation with solvent
(swelling ratio, mLgꢀ1) by the syringe method.[13b] The
lyophilized resin was weighed in a syringe fitted with a
Teflon filter and the solvent was added to the syringe; equi-
librium swelling was achieved in three hours at room tem-
perature. The swelling ratio, measured upon removal of all
excess solvent with the syringe piston, was reproducible with
an experimental error of <3%. The degree of swelling
(~6 mLgꢀ1) for differently cross-linked (10–15%) ULTRA-
MINE resin was determined (Figure S2a in the Supporting
Information). As expected, the swelling of ULTRAMINE
increases as the cross-linking density decreases. The resin
swelled efficiently in both polar and nonpolar solvents, rang-
ing from water to dichloromethane; swelling was more pro-
nounced in the protic solvents than in polar nonprotic and
nonpolar solvents. This is explained by the high concentra-
tion of functional amino groups. Strong cooperative hydro-
gen bonds induce an effect of additional cross-linking and
solvents that can disrupt hydrogen bonding can therefore
solvate the polymer more effectively. The rate of swelling is
an important factor for the performance of a solid support.
Dry ULTRAMINE polymers swell >95% in ten minutes,
which indicates that the resin could be useful for solid-phase
synthesis and scavenging processes.
EA0 ¼ limgA!0@sA=@gA
ð1Þ
Two examples of such stress–strain curves for single UL-
TRAMINE beads are given in Figure 2a and b. The average
compressive modulus of an ULTRAMINE bead was found
to be 0.45 MPa, which indicates that the resin is sufficiently
stable to withstand various mechanical manipulations during
organic synthesis. Furthermore, the compressive modulus of
the resin was equal to or better than that of many commer-
cially available polar resins (Figure 2c).
Exposing the polymer to various reagents and conditions
typical in organic synthesis demonstrated the chemical sta-
bility of ULTRAMINE. The resin was subjected to different
reagents including trifluoroacetic acid (100%), piperidine
(20% in N,N-dimethylformamide), 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU; 100%), butyl lithium in heptane (2.7m so-
lution), triflic anhydride (100%), saturated NaOH, and
BF3·Et2O (100%) for 48 hours at room temperature. No
macroscopic changes such as deformation of the beads or
change in particle size were observed. Neither did the treat-
ment induce any changes in the IR spectra of these samples
in comparison with those of the original resin (Figure S3 in
the Supporting Information). The swelling properties of the
resin after treatment with the reagents for two weeks also
did not show any significant changes from the original prop-
erties (Figure S2b in the Supporting Information). The resin
remained colorless and did not dissolve under any of these
harsh conditions.
Figure 2. Mechanical stability of ULTRAMINE beads. Apparent com-
pressive stress–apparent compressive strain plot for a) bead-size 350 mm
and b) bead-size 420 mm. The dotted lines represent linear regressions
used for calculation of the initial apparent modulus. Do is the bead diam-
eter of the relaxed bead and D is the diameter during compression. c) In-
itial apparent compressive modulus of ULTRAMINE (A) and commer-
cial resins: SPOCC 2000 (B), SPOCC 4000 (C), POEPOP 2000 (D), Se-
phadex G50 (E), Biogel P100 (F), and PEGA 1900 (G).
Mechanical stability of a polymer support is an important
property in solid-phase organic synthesis and scavenging
processes, particularly when they perform on a larger scale.
The mechanical stability of ULTRAMINE beads was deter-
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ULTRAMINE
4407 – 4415
Functional capacity of ULTRAMINE: The efficiency of a
resin used as scavenger depends on its functional capacity/
volume. The amino-function capacity of ULTRAMINE was
determined by derivatization with Fmoc-Gly-OH. The Fmoc
protecting group from a weighed amount of dry resin was
cleaved by 20% piperidine in MeOH, the UV absorbance of
the piperidine–dibenzofulvene adduct was determined, and
the adduct concentration equivalent to that of accessible
amino groups was calculated (Table 1). MeOH was used be-
cause of the favorable swelling properties in MeOH com-
pared to N,N-dimethylformamide. The number of accessible
functional groups increases as the percentage of cross-link-
ing decreases.
Synthesis of ULTRAMINE-Red: The available functional
amino groups on ULTRAMINE can be increased consider-
ably by the exhaustive reduction of amide groups. This ex-
haustive reduction was accomplished by using a mixture of
borane and trimethylborate, followed by quenching of
excess borane with piperidine.[26] In the IR spectra of the
resin after reduction the amide carbonyl signal had com-
pletely disappeared (Figure 3). The loading of primary and
secondary amino groups in the different reduced ULTRA-
MINE resins is presented in Table 1.
Figure 3. Comparison of the IR spectra of a) ULTRAMINE-Red and
b) ULTRAMINE.
resin that had fivefold available amino groups relative to the
excess acylating reagents. All the reactions and scavenging
yielded products with excellent conversion and purity
(Table 2). The HPLC profiles of crude products after treat-
ment with ULTRAMINE are presented in Figure S4 in the
Supporting Information.
ULTRAMINE as a scavengerresin : The amount of resin re-
quired for a scavenging process is important for the general
application of scavengers in solution-phase synthesis. When
the volume of the required
ULTRAMINE-Red as a scavengerresin : To explore the use
of ULTRAMINE-Red as a scavenger resin, we performed
scavenger is reduced due to in-
creased loading, the product
can be more easily washed out
quantitatively from the poly-
mer. Due to high functional
loading and sufficient swelling,
the ULTRAMINE polymer
serves as a very efficient scav-
enger resin. Scheme 2 illustrates
parallel solution-phase reac-
tions of an excess of acylating
agents with amines (2-aminobu-
tane, 3-aminopentane, 4-nitro-
aniline, and 3-phenyl-1-propyla-
mine). A 15% cross-linked UL-
TRAMINE was used for the ef-
fective removal of excess acyl-
ating agents and sequestering of
byproducts, for example, HCl
and
hydrolyzed
reagent
(Scheme 3). The reaction of a
2.5-fold excess of acylating
agents (acid chlorides, thiocya-
nates, chloroformates, and sul-
fonyl chlorides) with the
amines yielded amides, thiour-
eas, carbamates, and sulfona-
mides, respectively. The reac-
tion mixture was then separate-
ly treated with ULTRAMINE Scheme 2. Parallel reactions of amines with excess acylating reagents as examples for the use of scavengers.
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4411

M. Meldal et al.
FULL PAPER
the reaction of 3-aminopentane with a 2.5-fold excess of
phenyl isothiocyanate. The excess reagent was then scav-
enged by using ULTRAMINE-Red. In order to demonstrate
the amount of ULTRAMINE-Red required for scavenging
excess isothiocyanate (0.15 mmol), different amounts of
resin were used. The results revealed that only 10 mg of
resin were required for the complete scavenging of the iso-
thiocyanate (Figure 4). Approximately 22 mg of pure prod-
uct were obtained.
Figure 4. HPLC trace of the crude products obtained after scavenging
phenyl isothiocyanate with a) 10 mg of ULTRAMINE-Red and b) 5 mg
of ULTRAMINE-Red. Column: RCM C-18 (8”200 mm). Elution gradi-
ent: From 0–80% of buffer containing 0.1% trifluoroacetic acid in 10%
aqueous acetonitrile over 10 min at a flow rate of 5 mLminꢀ1. Detection:
215 nm.
Scheme 3. Use of ULTRAMINE as a scavenger resin for the rapid purifi-
cation of parallel amine acylation reactions.
Table 2. Yields [%]and purities [%]of solution-phase amide, urea, carbamate, thiourea, and sulfonamide
Conclusion
products 1–28 purified by ULTRAMINE scavenging of excess reagent and acidic byproducts.[a]
ULTRAMINE, a high-capacity
resin, was prepared by inverse
suspension
polymerization
1
8
15
22
through different ratios of par-
tial acryloylation of polyeth-
ylene–imine macromonomers.
The resin performs excellently
as a scavenger resin for solu-
tion-phase synthesis. It is stable
to a variety of harsh reaction
conditions used in conventional
organic synthesis. The resin is
chemically and mechanically
stable and can withstand differ-
ent acidic, basic, electrophilic,
and nucleophilic reaction condi-
tions.
99.7/100
99.5/100
99.5/100
99.5/100
2
9
16
97.2/100
23
97.4/100
99.0/98.5
96.3/100
3
10
94.8/100
17
96.1/100
24
95.8/100
99.2/100
4
11
92.8/95.4
18
92.4/94.9
25
94.0/95.6
96.3/96
5
12
90.7/94.1
19
96.3/93.3
26
92.4/92.3
97.5/94.6
ULTRAMINE showed
a
high degree of swelling in both
polar and less polar solvents; it
can be used as a scavenger
resin in both aqueous and non-
6
13
93.8/95.6
20
97.2/94.2
27
94.1/92.7
96.5/95.3
7
14
96.9/100
21
99.2/100
28
96.3/100
99.3/100
aqueous
reactions.
Amide
groups in ULTRAMINE were
quantitatively converted into
[a]For further details, see the Experimental Section. Chromatograms of representative products are presented
in the Supporting Information.
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ULTRAMINE
4407 – 4415
with argon for 30 min. Solutions of sorbitan monolaurate (0.5 mL) in
DMF (1 mL) and the free-radical initiator ammonium persulfate (0.5 g)
in water (2 mL) were added to the monomer mixture. The reaction mix-
ture was then rapidly added to the suspension medium stirred at 650 rpm
at 308C. After 1 min, sodium disulfide (0.05 g) in water (1 mL) and
TEMED (1 mL) were added simultaneously but separately to the reac-
tor. The reaction was allowed to continue for 3 h at 308C and the beads
that formed were filtered through a sieve, washed thoroughly with etha-
nol (10”), water (10”), and ethanol (10”). The resin was suspended in
10% DIPEA in ethanol for 4 h, washed with ethanol (10”), water (10”
), and ethanol (10”), and dried under high vacuum. Yield: 9.5 g (95%);
bead-size distribution: 300–500 mm 86%, 100–300 mm 12%, <100 mm
2%; compressive modulus: 0.44 MPa; color: transparent, pale yellow;
amino loading: 16.35 mmolgꢀ1; swelling: water 8.5, DMF 4.2 mLgꢀ1; IR:
amines by borane reduction to provide an all-amine resin
with up to 21 mmol of functional amino groups per gram.
Experimental Section
Synthesis of partially acryloylated polyethylene–imine polymers: Acrylo-
yl chloride (2.403 mL, 36 mmol) in dichloromethane (DCM; 12 mL) was
added dropwise to a solution of polyethylene–imine polymer (7.9 mL,
240 mmol of amino groups, Mw =423 gmolꢀ1) in DCM (18 mL) at 08C
with stirring. The reaction mixture was stirred for 1 h at 208C. The DCM
was evaporated, and drying in vacuo at 208C yielded 15% acyloylated
(of the total number of amine groups) polyethylene–imine polymer as a
thick, pale yellow oil. Acryloylated polyethylene–imine macromonomers
containing 13.5, 11.5, and 10% acryloylation were also prepared by using
2.1 (32), 1.9 (28), and 1.6 mL (24 mmol) of acryloyl chloride, respectively.
n˜ =3272.6 (NH stretch), 2937.1 (CH stretch), 1622.6 (CONH) cmꢀ1
.
Synthesis of ULTRAMINE with different cross-linking densities: The
polymerizations were performed in n-heptane (140 mL). Sorbitan mono-
laurate (0.5 mL in DMF) was used as the suspension stabilizer and am-
monium persulfate (0.5 g) in water (2 mL) was used as the free-radical in-
itiator. A degassed solution of partially acryloyated polyethylene–imine
polymer in water (25 mL) was mixed with suspension stabilizer and radi-
cal initiator and transferred to the degassed continuous phase stirred at
650 rpm and 708C. The promoter TEMED (1 mL) was added to the reac-
tion mixture after 1 min, and the reaction was allowed continue for 3 h.
The beads were filtered and washed thoroughly with ethanol (10”),
water (10”), and ethanol (10”). The resin was suspended in 10%
DIPEA in ethanol for 4 h, washed with ethanol (10”), water (10”), and
ethanol (10”), and dried under high vacuum.
Synthesis of ULTRAMINE
Bulk polymerization: 15% acyloylated ((Acr)15%) polyethylene–imine
macromonomer (5.00 g, 9.58 mmol) in water (5 mL) and ammonium per-
sulfate (0.25 g) in water (1 mL) were mixed in a round-bottomed flask
under argon. The reaction mixture was kept in a thermostated oil bath
maintained at 708C for 30 min. The white, hard, bulky polymer obtained
was washed with water (6”15 mL), MeOH (6”15 mL), EtOH (6”
15 mL), N,N-dimethylformamide (DMF; 6”15 mL), and DCM (6”
15 mL). The polymer was granulated through a 1 mm net and sieved.
The fine particles were removed by repeated decantation. The polymer
particles were characterized by microscope imaging. Yield: 4.82 g (97%);
(Acr)13.5% polyethylene–imine polymer (9.8 g, 19.2 mmol) yielded 8.9 g of
resin (91%); bead-size distribution: 300–500 mm 85%, 100–300 mm 12%,
<100 mm 3%; color: transparent, pale yellow; amino loading:
17.3 mmolgꢀ1; swelling: water 8.5, DMF 4.9 mLgꢀ1; IR: n˜ =3272.2 (NH
IR: n˜ =3272.3 (NH stretch), 2937.6 (CH stretch), 1622.8 (CONH) cmꢀ1
.
Inverse suspension polymerization in various continuous phases: UL-
TRAMINE was prepared by the inverse suspension polymerization
method. A mixture of n-heptane/carbon tetrachloride (6:4 (v/v), 140 mL)
was used as the continuous phase and added to the cylindrical polymeri-
zation flask containing bafflers and a 6-blade mechanical stirrer. The
flask was then heated in an oil bath at 708C. The continuous phase was
purged with argon for 10 min and stirred at a rate of 650 rpm. In a typical
procedure, a solution of (Acr)15% polyethylene–imine polymer (10 g,
19.16 mmol) in water (25 mL) was degassed with argon for 30 min. Solu-
tions of sorbitan monolaurate (0.5 mL) in DMF (1 mL) and ammonium
persulfate (0.5 g) in water (2 mL) were added to the monomer mixture
with stirring. The reaction mixture was then rapidly added to the suspen-
sion medium stirred at 650 rpm at 708C. After 1 min, TEMED (1 mL)
was added to the reactor. The reaction was allowed to continue for 3 h
and the beads formed were filtered through a sieve. They were washed
thoroughly with ethanol (10”), water (10”), and ethanol (10”). The
resin was suspended in 10% DIPEA in ethanol for 4 h, washed with eth-
anol (10”), water (10”), and ethanol (10”), and dried under high
vacuum. Yield: 9.5 g (95%); bead-size distribution: >500 mm 2%, 300–
500 mm 80%, 100–300 mm 15%, <100 mm 3%; compressive modulus:
stretch), 2937.3 (CH stretch), 1622.3 (CONH) cmꢀ1
.
(Acr)11.5% polyethylene–imine polymer (9.3 g, 18.6 mmol) yielded 8.1 g of
resin (87%); bead-size distribution: 300–500 mm 87%, 100–300 mm 10%,
<100 mm 3%; color: transparent, pale yellow; amino loading:
17.9 mmolgꢀ1; swelling: water 8.7, DMF 5.1 mLgꢀ1; IR: n˜ =3272.2 (NH
stretch), 2937.6 (CH stretch), 1622.2 (CONH) cmꢀ1
.
(Acr)10% polyethylene–imine polymer (10 g, 20.45 mmol) yielded 8 g of
resin (80%); bead-size distribution: 300–500 mm 85%, 100–300 mm 10%,
<100 mm 5%; color: transparent, pale yellow; amino loading:
18.6 mmolgꢀ1; swelling: water 9.0, DMF 5.5 mLgꢀ1; IR: n˜ =3272.2 (NH
stretch), 2937.3 (CH stretch), 1622.5 (CONH) cmꢀ1
.
Characterization
Loading: The amino functional loading was determined from the Fmoc-
derivatized resin. The resin (10 mg) was treated with DMF (500 mL) con-
taining Fmoc-Gly-OH (1m), O-benzotriazol-1-yl-N,N,N’,N’-tetramethy-
luronium tetrafluoroborate (TBTU; 0.94m) and N-ethylmorpholine (1m)
overnight. It was washed with DMF (10”), MeOH (10”), and DCM
(10”), then dried in vacuo. The resin (3–5 mg) was treated with piperi-
dine/MeOH solution (20% (v/v), 8 mL) for 30 min. The amino capacity
of the resin was calculated from the optical density value of the piperi-
dine–dibenzofulvene solution at 290 nm. The amino functional loading of
0.44 MPa; color: transparent, pale yellow; amino loading: 16.03 mmolgꢀ1
swelling: water 8.2, DMF 4.2 mLgꢀ1; IR: n˜ =3272.1 (NH stretch), 2937.4
(CH stretch), 1622.2 (CONH) cmꢀ1
;
.
The inverse suspension polymerization was carried out with n-heptane
(140 mL) as the continuous phase. The polymerization was performed
with same reagent amounts and conditions as above. Yield: 9.7 g (97%);
bead-size distribution: 300–500 mm 88%, 100–300 mm 10%, <100 mm
2%; compressive modulus: 0.45 MPa; color: transparent, pale yellow;
amino loading: 16.5 mmolgꢀ1; swelling: water 8.4, DMF 4.6 mLgꢀ1; IR:
15% cross-linked ULTRAMINE was measured to be 16.5 mmolgꢀ1
.
Swelling: The swelling capabilities of the resin in different solvents were
determined by the syringe method. In a typical procedure, a dry sample
of the resin (100 mg) was taken up in a 2 mL syringe fitted with a Teflon
filter at the bottom. The appropriate solvent was sucked into the syringe
and after 3 h, excess solvent was removed by applying force on the
piston. The extent of swelling of the resin in each solvent was determined
from the ratio of the volume of the solvent absorbed during incubation
and the weight of dry resin.
n˜ =3272.3 (NH stretch), 2937.4 (CH stretch), 1622.2 (CONH) cmꢀ1
.
The inverse suspension polymerization was carried out with Isopar M
(140 mL) as the continuous phase. The polymerization was performed
with same reagent amounts and conditions as above. Yield: 9.6 g (96%);
bead-size distribution: 300–500 mm 83%, 100–300 mm 15%, <100 mm
2%; compressive modulus: 0.45 MPa; color: transparent, pale yellow;
amino loading: 16.25 mmolgꢀ1; swelling: water 8.4, DMF 4.3 mLgꢀ1; IR:
Chemical stability: The chemical stability of the resin was determined in
different reagents including trifluoroacetic acid (100%), 20% piperidine
in DMF, DBU (100%), butyl lithium (2.7m solution in heptane, 100%),
triflic anhydride (100%), saturated NaOH, and BF3·Et2O (100%). The
resin samples (100 mg) were separately stirred with the reagents for 48 h
at room temperature. The treated resin was visually inspected for macro-
scopic changes. The resin was filtered, washed, and dried. IR spectra
were recorded and compared with the spectra of the original resin (Fig-
n˜ =3272 (NH stretch), 2937.6 (CH stretch), 1622.5 (CONH) cmꢀ1
.
Isopar M (140 mL) was used as the continuous phase and polymerization
performed at 308C. The continuous phase was purged with argon for
10 min and stirred at a rate of 650 rpm. A solution of (Acr)15% polyeth-
ylene–imine polymer (10 g, 19.16 mmol) in water (25 mL) was degassed
Chem. Eur. J. 2004, 10, 4407 – 4415
www.chemeurj.org
ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4413

M. Meldal et al.
FULL PAPER
ure S3 in the Supporting Information). The swelling properties of the
resin after treatment with the reagents for two weeks were also com-
pared to the original properties. The resin did not dissolve under any of
these conditions and showed no changes in color or swelling, a result in-
dicating that no significant bond cleavage had occurred.
N-(2-Butyl)-N’-phenylthiourea (7): White crystalline solid (20.66 mg,
99.3%); m.p. 105–1068C; 1H NMR (250 MHz, CDCl3): d=0.83 (t, 3H),
1.09 (d, 3H), 1.35–1.48 (brs, 2H), 4.22–4.35 (brs, 1H), 5.65 (s, 1H), 7.05–
7.55 (brs, 5H) ppm; ESI MS: m/z calcd: 259.07; found: 259.1 [M+H]+.
N-(3-Pentyl)ethanamide (8): Colorless oil (12.84 mg, 99.5%); 1H NMR
(250 MHz, CDCl3): d=0.95 (t, 6H), 1.12–1.58 (brs, 4H), 1.68 (s, 3H),
2.91 (brs, 1H), 8.22 (s, 1H) ppm; ESI MS: m/z calcd: 130.12; found:
130.1 [M+H]+.
N-(3-Pentyl)hexanamide (9): Colorless oil (17.83 mg, 96.3%); 1H NMR
(250 MHz, CDCl3): d=0.81 (t, 3H), 1.02 (t, 6H), 1.11–1.25 (brs, 2H),
1.38–1.62 (brs, 4H), 1.66–1.88 (brs, 4H), 2.04 (t, 2H), 2.95 (brs, 1H),
8.25 (s, 1H) ppm; ESI MS: m/z calcd: 186.18; found: 186.1 [M+H]+.
Mechanical stability: A bead (300–500 mm) was placed between a ccd
camera lens and a cylindrical probe, connected to a strain gauge, to meas-
ure the force applied, and an actuator; the sample was then compressed
at a constant rate of 10 mmminꢀ1. The camera recorded the deformation
of the bead. An apparent compressive modulus (EA), can then be calcu-
lated as the ratio of the apparent compressive stress (sA, the force per
area of cross section of the bead) over the apparent compressive strain
(gA, the ratio of the diameter over the initial diameter).
N-(3-Pentyl)benzamide (10): White crystalline solid (18.12 mg, 94.8%);
m.p. 136–1378C; 1H NMR (250 MHz, CDCl3): d=1.02 (t, 6H), 1.39–1.68
(brs, 4H), 2.93 (brs, 1H), 7.25–7.65 (brs, 5H), 8.25 (s, 1H) ppm; ESI
MS: m/z calcd: 192.13; found: 192.1 [M+H]+.
Synthesis of ULTRAMINE-Red: The resin (500 mg, containing 1.6 mmol
of carbonyl groups) and boric acid (0.6 g, 9.6 mmol, 6 equiv) were meas-
ured into a reaction vessel. Trimethylborate (1 mL, 9.6 mmol, 6 equiv)
was added; this was followed by addition of 1m borane–THF complex
(32 mL, 20 equiv). After cessation of hydrogen evolution, the tubes were
capped tightly and kept in an oil bath at 658C for 72 h. The resin was
then filtered and washed with DMF (4”10 mL) and MeOH (4”10 mL).
The resin was suspended in piperidine (100%, 10 mL) and heated at
658C for 20 h to destroy the excess borane. The piperidine–borane solu-
tion was decanted, then the resin was washed with DMF (4”10 mL),
DCM (4”10 mL), and MeOH (4”10 mL) and dried under vacuum to
provide ULTRAMINE-Red with a quantitative conversion of amides to
amines, as monitored by the complete disappearance of the carbonyl
bands in the IR spectrum. Loadings are presented in Table 1; compres-
sive modulus: 0.45 MPa; color: transparent, pale yellow; IR: n˜ =3272.3
N-(4-Nitrophenyl)-N’-(3-pentyl)thiourea (11): Yellow crystalline solid
(24.78 mg, 92.8%); m.p. 112–1148C; 1H NMR (250 MHz, CDCl3): d=
0.88 (t, 6H), 1.45–1.69 (brs, 4H), 4.25 (brs, 1H), 7.23–7.61 (brs, 4H),
8.15 (brs, 2H) ppm; ESI MS: m/z calcd: 268.1; found: 268 [M+H]+.
9-Fluorenylmethyl-3-pentylcarbamate (12): White crystalline solid
(28.04 mg, 90.7%); m.p. 126–1288C; 1H NMR (250 MHz, CDCl3): d=
0.84 (t, 6H), 1.24–1.58 (brs, 4H), 3.48 (brs, 1H), 4.25 (t, 1H), 4.45 (d,
2H), 7.20–7.80 (brs, 8H) ppm; ESI MS: m/z calcd: 310.17; found: 310.1
[M+H]+.
2-Nitro-N-(3-pentyl)benzenesulfonamide (13): Brown crystalline solid
(25.52 mg, 93.8%); m.p. 178–1818C; 1H NMR (250 MHz, CDCl3): d=
0.74 (t, 6H), 1.28–1.68 (brs, 4H), 3.25 (brs, 1H), 5.05 (s, 1H), 7.61–8.18
(brs, 4H) ppm; ESI MS: m/z calcd: 223.12; found: 223.1 [M+H]+.
(NH stretch), 2937.6 (CH stretch) cmꢀ1
.
General procedure for acylation/scavenging: All the compounds were
synthesized simultaneously in a parallel arrangement (Table 2). Acylating
reagents (0.25 mmol) were added to 10 mL plastic vials, each containing
amine (0.1 mmol) in dry DCM (1 mL). Each vial was closed tightly, and
the mixture was agitated at room temperature with a shaker for 16 h.
ULTRAMINE (50 mg) was added to each vial and the solution was dilut-
ed to a volume of 3 mL with DCM. The resulting mixture was then agi-
tated for 6 h at room temperature and filtered. The resin was washed
with DCM (4”4 mL). The combined filtrate and washings were concen-
trated and transferred to a vial, and the solvent was removed with a
stream of argon. The resulting product was dried under vacuum over-
night to provide the product in almost quantitative yield. The purity of
each product was analyzed by HPLC (Table 2).
N-(2-Butyl)ethanamide (1): Colorless oil (11.47 mg, 99.7%); 1H NMR
(250 MHz, CDCl3): d=0.84 (t, 3H), 1.07 (d, 3H), 1.375–1.575 (brs, 2H),
1.88 (s, 3H), 3.97 (brs, 1H), 8.32 (s, 1H) ppm; ESI MS: m/z calcd: 116.1;
found: 116.1 [M+H]+.
N-(2-Butyl)hexanamide (2): Colorless oil (16.94 mg, 99.0%); 1H NMR
(250 MHz, CDCl3): d=0.84 (t, 3H), 0.88 (t, 3H), 1.12 (d, 3H), 1.23–1.37
(brs, 4H), 1.54–1.56 (brs, 4H), 2.05 (t, 2H), 3.84 (brs, 1H), 8.15 (s,
1H) ppm; ESI MS: m/z calcd: 172.16; found: 172.1 [M+H]+.
N-Phenyl-N’-(3-pentyl)thiourea (14): White crystalline solid (21.52 mg,
96.9%); m.p. 110–1128C; 1H NMR (250 MHz, CDCl3): d=0.85 (t, 6H),
1.28–1.54 (brs, 4H), 4.22 (brs, 1H), 7.26–7.66 (brs, 5H) ppm; ESI MS:
m/z calcd: 273.08; found: 273.1 [M+H]+.
N-(4-Nitrophenyl)ethanamide (15): Pale yellow crystalline solid
(17.91 mg, 99.5%); m.p. 212–2138C; 1H NMR (250 MHz, CDCl3): d=
2.13 (s, 3H), 7.55–7.62 (brs, 2H), 8.10–8.14 (brs, 2H) ppm; ESI MS: m/z
calcd: 181.05; found: 181 [M+H]+.
N-(4-Nitrophenyl)hexanamide (16): Pale yellow crystalline solid
(22.95 mg, 97.2%); m.p. 271–2738C; 1H NMR (250 MHz, CDCl3): d=
0.82 (t, 3H), 1.23–1.30 (brs, 4H), 1.65 (brs, 2H), 2.30 (t, 2H), 7.38 (s,
1H), 7.60–7.66 (brs, 2H), 8.10–8.18 (brs, 2H) ppm; ESI MS: m/z calcd:
237.12; found: 237 [M+H]+.
N-(4-Nitrophenyl)benzamide (17): Pale yellow crystalline solid (23.26 mg,
96.1%); m.p. 160–1628C; 1H NMR (250 MHz, CDCl3): d=7.30–7.60
(brs, 4H), 7.75–8.20 (brs, 5H) ppm; ESI MS: m/z calcd: 242.9; found:
243.0 [M+H]+.
N,N’-(Bis-4-nitrophenyl)thiourea (18): Yellow crystalline solid (29.38 mg,
92.4%); m.p. 186–1888C; 1H NMR (250 MHz, CDCl3): d=7.15–7.32
(brs, 4H), 7.92–8.20 (brs, 4H) ppm; ESI MS: m/z calcd: 319.04; found:
319 [M+H]+.
N-(2-Butyl)benzamide (3): White crystalline solid (17.57 mg, 99.2%);
m.p. 143–1458C; 1H NMR (250 MHz, CDCl3): d=0.88 (t, 3H), 1.12 (d,
3H), 1.38–1.65 (brs, 2H), 4.05 (brs, 1H), 7.31–7.72 (brs, 5H), 8.25 (s,
1H) ppm; ESI MS: m/z calcd: 178.12; found 178.1 [M+H]+.
9-Fluorenylmethyl-4-nitrophenylcarbamate (19): Pale yellow crystalline
solid (34.67 mg, 96.3%); m.p. 153–1558C; 1H NMR (250 MHz, CDCl3):
d=4.16 (d, 2H), 4.20 (brs, 1H), 7.01–7.75 (brs, 12H) ppm; ESI MS: m/z
calcd: 361.11; found: 361.1 [M+H]+.
N-(2-Butyl)-N’-(4-nitrophenyl)thiourea (4): Yellow crystalline solid
(24.37 mg, 96.3%); m.p. 119–1208C; 1H NMR (250 MHz, CDCl3): d=
0.89 (t, 3H), 1.15 (d, 3H), 1.55 (brs, 2H), 4.29 (brs, 1H), 7.18–8.15 (brs,
4H) ppm; ESI MS: m/z calcd: 254.09; found: 254.1 [M+H]+.
2-Nitro-N-(4-nitrophenyl)benzenesulfonamide (20): Brown crystalline
solid (26.53 mg, 97.2%); m.p. 252–2548C; 1H NMR (250 MHz, CDCl3):
d=7.45–7.88 (brs, 4H), 8.05–8.15 (brs, 4H) ppm; ESI MS: m/z calcd:
274.03; found: 274 [M+H]+.
N-(4-Nitrophenyl)-N’-phenylthiourea (21): Yellow crystalline solid
(32.04 mg, 99.2%); m.p. 144–1458C; 1H NMR (250 MHz, CDCl3): d=
7.10–7.22 (brs, 5H), 7.92–8.12 (brs, 4H) ppm; ESI MS: m/z calcd:
324.02; found: 324 [M+H]+.
9-Fluorenylmethyl-2-butylcarbamate (5): Pale yellow crystalline solid
(28.77 mg, 97.5%); m.p. 163–1658C; 1H NMR (250 MHz, CDCl3): d=
0.84 (t, 3H), 1.31 (d, 3H), 1.55–1.78 (brs, 2H), 4.1 (t, 1H), 4.20–4.35 (brs,
1H), 4.41 (d, 2H), 7.22–7.72 (brs, 8H), 8.23 (s, 1H) ppm; ESI MS: m/z
calcd: 296.16; found: 296.1 [M+H]+.
N-(3-Phenylpropyl)ethanamide (22): Colorless oil (17.65 mg, 99.5%);
1H NMR (250 MHz, CDCl3): d=1.72 (brs, 2H), 1.92 (s, 3H), 2.55 (brs,
2H), 3.23 (brs, 2H), 7.10–7.30 (brs, 5H), 8.05 (s, 1H) ppm; ESI MS: m/z
calcd: 178.12; found: 178.1 [M+H]+.
N-(2-Butyl)-2-nitrobenzenesulfonamide (6): Brown crystalline solid
(24.9 mg, 96.5%); m.p 181–1838C; 1H NMR (250 MHz, CDCl3): d=0.78
(t, 3H), 1.05 (d, 3H), 1.35–1.45 (brs, 2H), 3.31–3.58 (brs, 1H), 5.05 (s,
1H), 7.42–7.88 (brs, 4H) ppm; ESI MS: m/z calcd: 209.1; found 209.1
[M+H]+.
N-(3-Phenylpropyl)hexanamide (23): Colorless oil (22.71 mg, 97.4%);
1H NMR (250 MHz, CDCl3): d=0.82 (t, 3H), 1.15–1.25 (brs, 2H), 1.48
4414
ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2004, 10, 4407 – 4415

ULTRAMINE
4407 – 4415
(brs, 2H), 1.64–2.71 (brs, 8H), 3.24 (brs, 2H), 7.05–7.32 (brs, 5H), 8.14
Frankel, D. V. Santi, F. E. Cohen, P. A. Bartlett, Proc. Natl. Acad.
Sci. USA 1992, 89, 9367–9371.
(s, 1H) ppm; ESI MS: m/z calcd: 234.18; found: 234.1 [M+H]+.
[4]G. T. Wang, S. Li, N. Wideburg, G. A. Krafft, D. J. Kempf, J. Med.
Chem. 1995, 38, 2995–3002.
N-(3-Phenylpropyl)benzamide (24): White crystalline solid (22.9 mg,
95.8%); m.p. 157–1598C; 1H NMR (250 MHz, CDCl3): d=1.85 (brs,
2H), 2.58 (t, 2H), 3.38 (brs, 2H), 7.15–7.65 (brs, 10H), 8.20 (s, 1H) ppm;
ESI MS: m/z calcd: 240.13; found: 240.1 [M+H]+.
[5]a) Polymer-Supported Reactions in Organic Synthesis (Eds.: P.
Hodge, D. Sherrington), John Wiley and Sons, Chichester, UK,
1980; b) Solid Phase Peptide Synthesis: A Practical Approach (Eds.:
E. Atherton, R. C. Sheppard), Oxford University Press, New York,
1989.
N-(4-Nitrophenyl)-N’-(3-phenylpropyl)thiourea (25): Yellow crystalline
1
solid (29.61 mg, 94%); m.p. 117–1188C; H NMR (250 MHz, CDCl3): d=
1.95 (brs, 2H), 2.60 (t, 2H), 3.60 (brs, 2H), 7.10–8.15 (brs, 9H) ppm; ESI
[6]M. Meldal in Methods in Enzymology, Vol. 289 (Ed.: G. B. Fields),
Academic Press, San Diego, 1997, pp. 83–104.
MS: m/z calcd: 316.1; found: 316 [M+H]+.
9-Fluorenylmethyl-(3-phenylpropyl)carbamate (26): White crystalline
solid (33 mg, 92.4%); m.p. 98–1008C; 1H NMR (250 MHz, CDCl3): d=
1.71 (brs, 2H), 2.55 (t, 2H), 3.10 (brs, 2H), 3.95 (brs, 1H), 4.28 (d, 2H),
7.10–7.75 (brs, 13H) ppm; ESI MS: m/z calcd: 358.17; found: 358.1
[M+H]+.
[7]a) S. Zalipsky, J. L. Chang, F. Albericio, G. Barany, React. Polym.
1994, 22, 243–258; b) H. Hellerman, H. W. Lucas, J. Maul, V. N. R.
Pillai, M. Mutter, Makromol. Chem. 1983, 184, 2603–2617.
[8] The Chemistry of Peptides and Proteins Vol. 3, Proceedings of the
Fifth USSR-FRG Symposium on Chemistry of Peptides and Pro-
teins, Odessa, USSR, May 16–20, 1985; (Eds.: W. Voelter, E. Bayer,
Yu. A. Ovchinnikov, V. T. Ivanov), Walter de Gruyter & Co., Berlin,
1986.
[9]a) M. Renil, R. Nagaraj, V. N. R. Pillai, Tetrahedron 1994, 50, 6681–
6688; b) J. T. Varkey, V. N. R. Pillai, J. Pept. Res. 1998, 51, 49–54;
c) M. Roice, K. S. Kumar, V. N. R. Pillai, Macromolecules 1999, 32,
8807–8815.
[10]a) M. Renil, M. Meldal, Tetrahedron Lett. 1996, 37, 6185–6188; b) J.
Buchardt, M. Meldal, Tetrahedron Lett. 1998, 39, 8695–8698.
[11]P. H. Toy, K. D. Janda, Tetrahedron Lett. 1999, 40, 6329–6332.
[12]a) E. Atherton, D. L. J. Clive, R. C. Sheppard, J. Am. Chem. Soc.
1975, 97, 6584–6585; b) R. Arshady, E. Atherton, D. L. J. Clive,
R. C. Sheppard, J. Chem. Soc. Perkin Trans. 1 1981, 529–537.
[13]a) M. Meldal, Tetrahedron Lett. 1992, 33, 3077–3080; b) F. I. Auzan-
neau, M. Meldal, K. Bock, J. Pept. Sci. 1995, 1, 31–44.
[14]J. Buchardt, M. Meldal, Tetrahedron Lett. 1998, 39, 8695–8698.
[15]J. Rademann, M. Grøtli, M. Meldal, K. Bock, J. Am. Chem. Soc.
1999, 121, 5459–5466.
2-Nitro-N-(3-phenylpropyl)benzenesulfonamide (27): Brown crystalline
solid (25.41 mg, 94.1%); m.p. 175–1788C; 1H NMR (250 MHz, CDCl3):
d=1.76 (brs, 2H), 2.50 (t, 2H), 3.05 (brs, 2H), 5.25 (s, 1H), 6.90–7.68
(brs, 9H) ppm; ESI MS: m/z calcd: 271.12; found: 271.1 [M+H]+.
N-Phenyl-N’-(3-phenylpropyl)thiourea (28): White crystalline solid
(30.82 mg, 96.3%); m.p. 210–2128C; 1H NMR (250 MHz, CDCl3): d=
1.85 (brs, 2H), 2.56 (t, 2H), 3.55 (brs, 2H), 7.05–7.39 (brs, 10H) ppm;
ESI MS: m/z calcd: 321.08; found: 321 [M+H]+.
ULTRAMINE-Red as
a scavenger: Phenyl isothiocyanate (30 mL,
0.25 mmol) was added to 10 mL plastic vials, each containing 3-amino-
pentane (11.7 mL, 0.1 mmol) in dry DCM (1 mL). Each vial was closed
tightly, and the mixture was agitated at room temperature with a shaker
for 16 h. ULTRAMINE-Red (50, 40, 25, 10, or 5 mg) was added to each
vial and the solution was diluted to a volume of 3 mL with DCM. The re-
sulting mixture was then agitated for 6 h at room temperature and fil-
tered. The resin was washed with DCM (4”4 mL). The combined filtrate
and washings were concentrated and transferred to a vial, and solvent
was removed with a stream of argon to yield the product in an almost
quantitative yield upon lyophilization for 16 h. The purity of products
was analyzed by HPLC (Figure 4 presents the HPLC analyses for 5 and
10 mg resin), and the results indicated that 10 mg of ULTRAMINE-Red
was sufficient to act as a scavenger.
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Acknowledgement
This work was carried out at the Center for Solid Phase Organic Combi-
natorial Chemistry (SPOCC) and was supported by the Danish National
Research Foundation. The authors would also like to thank Combio A/S
and VersaMatrix A/S for a fellowship to M.R. The help rendered by Dr.
Charlotte H. Gotfredsen in recording the MAS NMR spectra is gratefully
acknowledged.
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Received: March 30, 2004
Published online: July 28, 2004
Chem. Eur. J. 2004, 10, 4407 – 4415
www.chemeurj.org
ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4415