High-load, oligomeric monoamine hydrochloride: facile generation via ROM polymerization and application as an electrophile scavenger

Article abstract of DOI:10.1016/j.tetlet.2008.05.011

A new high-load, oligomeric monoamine hydrochloride (OMAm·HCl) derived from ring-opening metathesis polymerization (ROMP) of norbornene methylamine is reported. This oligomeric amine has been shown to be an effective scavenger of acid chlorides, sulfonyl chlorides, and isocyanates. The reagent can be synthesized in a straightforward protocol from the Diels-Alder reaction of dicyclopentadiene (DCPD) 1 with allylamine (neat), formation of the corresponding ammonium salt and subsequent ROM polymerization to afford the desired oligomeric ammonium salts.

Full text of DOI:10.1016/j.tetlet.2008.05.011

Tetrahedron Letters 49 (2008) 4553–4555
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
High-load, oligomeric monoamine hydrochloride: facile generation via
ROM polymerization and application as an electrophile scavenger
Diana S. Stoianova a, Lei Yao a, Alan Rolfe b,c, Thiwanka Samarakoon b,c, Paul R. Hanson b,c,
*
a Materia Inc., 60 N. San Gabriel Blvd., Pasadena, CA 91107, USA
b Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582, USA
c KU Center of Excellence in Chemical Methodologies and Library Development, University of Kansas, 1501 Wakarusa Drive, Lawrence, KS 66047, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A new high-load, oligomeric monoamine hydrochloride (OMAmÁHCl) derived from ring-opening meta-
thesis polymerization (ROMP) of norbornene methylamine is reported. This oligomeric amine has been
shown to be an effective scavenger of acid chlorides, sulfonyl chlorides, and isocyanates. The reagent
can be synthesized in a straightforward protocol from the Diels–Alder reaction of dicyclopentadiene
(DCPD) 1 with allylamine (neat), formation of the corresponding ammonium salt and subsequent ROM
polymerization to afford the desired oligomeric ammonium salts.
Received 19 March 2008
Revised 2 May 2008
Accepted 5 May 2008
Available online 9 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
eration of high-load, immobilized reagents with tunable properties
to overcome the aforementioned limitations.5,6 We herein report
The growing demand for facile protocols to produce libraries of
compounds for high throughput screening related to drug discov-
ery has led to considerable efforts toward the development of
new enabling techniques.1,2 In this regard, immobilized reagents/
scavengers have emerged as effective tools which streamline puri-
fication by sequestering remaining reactant/reagents, leaving the
desired pure product in solution.3 While resin-based solid phase
organic chemistry (SPOC) has merits for offering a direct purifica-
tion technique, and is highly amenable to automation, it also pre-
sents limitations. Two primary deficiencies are the low-load levels
of reactive functionality in traditional solid phase resins (typically
1 mmol/g) and non-ideal reaction kinetics due to heterogeneous
reaction conditions. These problems are further compounded by
restrictions in both the types of solvents that can be used with each
resin and extended validation times required when transferring or
optimizing solution-phase organic reaction protocols to the hetero-
geneous environment of resin-based SPOC synthesis.
the development and application of a new high-load, oligomeric
monoamine hydrochloride (OMAmÁHCl) 4a which can be produced
on large scale from combination of Diels–Alder and ROMP
methodologies.
2. Results and discussion
Our interest in the synthesis of a high-load norbornenyl-tagged
amine scavenger was based on the desire to develop a complimen-
tary high-load, nucleophilic scavenger to augment electrophilic
scavengers previously reported.7 Resin-based amine scavengers
are well known to scavenger/sequester commonly used electro-
philes such as acid chlorides, sulfonyl chlorides, isocyanates, anhy-
drides, and chloroformates.8 With this goal in mind, we targeted
the oligomeric monoamine 4 shown in Scheme 1. A quick calcula-
tion reveals the high-load nature of the targeted oligomeric ROMP
In order to circumvent these issues, efforts have been directed
toward the development of new designer polymeric reagents and
scavengers with tunable properties.2 Despite significant advances,
resin limitations in nonlinear reaction kinetics, low resin-load
capacities, means of distributing reagents, and ‘technological
mechanics’ behind automating multi-step parallel solution-phase
sequences continue to warrant the development of novel platforms
and improved strategies. Among several technologies that have
emerged, ring-opening metathesis (ROM) polymerization4 of func-
tionalized norbornenes has surfaced as a powerful tool in the gen-
NH2
HA
NH2
NH2• HA
90-98%
172 °C
3
1
2
70%
CH2Cl2
NH2• HX
NH2• HA
Oligomeric Amine
Hydrochloride OMAm
OMAm•HCl (4a), 6.3 mmol/g
OMAm•TsOH (4b), 3.6 mmol/g
Mes
N
N
Mes
Ph
4
Cl
Ru
Cat-B
n
Cl
PCy3
* Corresponding author. Tel.: +1 785 864 3094; fax: +1 785 864 5396.
E-mail address: phanson@ku.edu (P. R. Hanson).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.011

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D. S. Stoianova et al. / Tetrahedron Letters 49 (2008) 4553–4555
scavenger 4 with a theoretical load of 8.3 mmol/g as the free
amine. This value represents a significant advantage over commer-
cially available electrophile scavengers: 1.3–1.5 mmol/g for PS-
NH2 (polystyrene), 3–5 mmol/g for PS-Trisamine and 2–3 mmol/g
for MP-Trisamine (macroporous, Biotage).9
the excess benzyl chloride was scavenged with 1.5 equiv of
2GOMAmÁHCl. After 2 h at room temperature, the crude reaction
mixture was added to a SiO2 SPE, and flushed with a solvent mix-
ture of 1:1 EtOAc/hexane. The resulting solution gave the desired
amides in good yield and purity. When K2CO3 was used as the base,
the reaction times for the scavenging event were longer, but work-
up involved only a simple filtration through Celite. Additionally,
we demonstrated the application of 2GOMAmÁHCl for the scaveng-
ing of excess sulfonyl chlorides in the sulfonylation of amines
(Table 1, entries 7–9). It is worthy to note that only 210 mg
(1.5 equiv) of the OMAmÁHCl was needed to scavenge 1 mmol of
the electrophile. In comparison, at least 1.0 g (3 equiv) of commer-
cially available resin Argoresin MP-Trisamine (Biotage, 2–3 mmol/
g)9 is required for complete consumption of the same amount of
electrophile. These data reinforce empirical evidence that ROMP
reagents possess characteristics on the fringe between small
molecules and that of insoluble polymers.
In addition to acid chlorides, OMAmÁHCl was also applied as a
scavenger to remove excess isocyanate and aldehydes yielding
the desired product in good yields and purity (Table 1, entries
10–13) (see Scheme 2).
In conclusion, we have synthesized a high-load, oligomeric
amine hydrochloride scavenger (4a) on multi-gram scale from
inexpensive starting materials that is highly amenable to kilogram
scale-up. The utility of these scavengers for scavenging/sequester-
ing of an assortment of electrophiles has been demonstrated.
Ultimately, this reagent has application in facilitated protocols
for library production avoiding tedious work-up procedures.
The direct synthesis of 4 was envisioned to occur via Diels–
Alder reaction of cyclopentadiene with allylamine followed by
ROM polymerization. However, it has been well documented that
metathesis of free primary amines is problematic.10 To circumvent
this problem, we targeted the oligomeric monoamine hydrochlo-
ride 4a and envisioned its use as a scavenger in the presence of
excess base to generate the free amine in situ. Monomeric
ammonium salts have been previously shown to undergo facile
ROM polymerization.11 In this regard, the free monomeric amine
2 was readily prepared by the Diels–Alder reaction of dicyclopent-
adiene (DCPD) 1 with allylamine (neat) in good yield and purity
after distillation. The norbornene ammonium salts were prepared
by treatment with the corresponding acid. ROM polymerization
of the norbornene ammonium salts was achieved by subjecting
the hydrochloride salt 3 with the second generation Grubbs
catalyst cat-B in monomer:catalyst ratios of 25–70:1.12 The pure
oligomeric monoamine hydrochloride cat-B (2GOMAmÁHCl, theo-
retical load 6.3 mmol/g) was found to have low solubility in DCM
and was isolated by filtration after treatment with ethyl vinyl
ether. Polymerization of the acetate, tosylate, and the bis(trimeth-
ylsilyl)amide derivatives of 1 was attempted as well. Treatment of
the acetate of 3 with catalyst cat-B (monomer:catalyst ratio = 30:1)
gave only starting material. The bis(trimethylsilyl)amide of 3 was
also prepared and ROM polymerization with cat-B yielded a
mixture of the desired polymer and starting material. The tosylate
of 3 polymerized cleanly with cat-B (monomer:catalyst ratios =
20–40:1) to yield 2GOMAmÁTsOH 4b.
Acknowledgments
This investigation was generously supported by funds provided
by the NIH STTR Grant (R41 GM076765 STTR-Phase-I), NIH COBRE
award (P20 RR015563) and the National Institutes of General
Medical Sciences (KU Chemical Methodologies and Library
Development Center of Excellence, P50 GM069663).
We found that although OMAmÁHCl has limited solubility in
most organic solvents including CH2Cl2, scavenging reactions were
fast and required only a slight excess of the scavenging reagent.
The benzoylation of a number of amines was investigated using
an excess of benzoyl chlorides in the presence of 3 equiv of base
(Table 1, entries 1–6).13 Upon completion of the reaction,
References and notes
NH2.HX
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Int. Ed. 2001, 40, 650–679; (d) Eames, J.; Watkinson, M. Eur. J. Org. Chem. 2001,
1213–1224.
(1.3 - 1.5 eq.)
R1NHR2
R2X
R1X (2 eq.)
Scavenge
R1NHR2
Pure
R1NH2
Et3N (3.1 eq.)
Filter
2. (a) Gravert, D. J.; Janda, K. D. Chem. Rev. 1997, 97, 489–509; (b) Toy, P. H.; Janda,
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D. L.; Hanson, P. R. Aldrichim. Acta 2005, 38, 3–16; (b) Zhang, M.; Flynn, D. L.;
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Scheme 2.
Table 1
Formation of substituted amines using 2GOMAmÁHCl (4a)a
Entry
R1NH2
R2X
Yielda (%)
Purityb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
iPrNH2
BnNH2
BnC(O)Cl
BnC(O)Cl
BnC(O)Cl
94
96
92
94
93
92
98
96
92
94
96
90
91
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
Pyrrolidine
iPrNH2
4-MeOBnCl
2,3-MeOBnCl
4-NO2BnCl
TsCl
2-BrBnSO2Cl
2-Br-4CF3-BnSO2Cl
PhNCO
4-MePhNCO
BnCHO
4-MeOBnCHO
iPrNH2
iPrNH2
BnNH2
BnNH2
BnNH2
4-MeBnNH2
4-MeBnNH2
4-MeBnNH2
4-MeBnNH2
7. (a) Herpel, R. H.; Vedantham, P.; Flynn, D. L.; Hanson, P. R. Tetrahedron Lett.
2006, 47, 6429–6432; (b) Moore, J. D.; Byrne, R. J.; Vedantham, P.; Flynn, D. L.;
Hanson, P. R. Org. Lett. 2003, 5, 4241–4244; (c) Moore, J. D.; Herpel, R. H.;
Lichtsinn, J. R.; Flynn, D. L.; Hanson, P. R. Org. Lett. 2003, 5, 105–107.
a
All reactions were carried out on 0.164 mmol scale, with addition of 1.5 equiv of
4a, unless stated otherwise.
b
Purity by 1H NMR of crude isolated products.

D. S. Stoianova et al. / Tetrahedron Letters 49 (2008) 4553–4555
4555
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9. Biotage: http://www.biotage.com/.
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degassed with argon for 15 min. Metathesis catalyst cat-B (177 mg,
0.21 mmol) was added and the mixture refluxed under argon until the
reaction was completed. The mixture was cooled, ethyl vinyl ether (5 ml) was
added and the mixture stirred for 30 min. The oligomer was filtered, washed
with CH2Cl2, and dried under high vacuum to afford 5.0 g as a free-flowing
off-white solid.
13. General procedure for the benzoylation of amines, followed by scavenging with
4a: Benzoyl chloride (38.1 ll, 0.33 mmol, 2 equiv) was added to a solution of
benzylamine (17.9 ll, 0.164 mmol, 1 equiv), Et3N (68.5 ll, 0.49 mmol, 3 equiv)
and CH2Cl2 (0.36 ml, 0.46 M). After stirring for 2 h, OMAm50 (41.9 mg,
0.26 mmol, 1.5 equiv) was added and stirring was continued for two
12. General procedure for the polymerization of the ammonium salts:
A
additional hours. The reaction was filtered through
hexane/EtOAc (1:1) to yield the desired product.
a SiO2 SPE using a
suspension of the hydrochloride salt (5 g, 31.3 mmol) in DCM (200 ml) was