High-load, oligomeric phosphonyl dichloride: facile generation via ROM polymerization and application to scavenging amines

Article abstract of DOI:10.1016/j.tetlet.2006.06.130

A new ROMP-derived scavenging reagent, oligomeric phosphonyl dichloride (OPC), with high-load and selectivity is reported. This reagent can be readily generated via the ROM polymerization of bicyclo[2.2.1]hept-5-en-2-ylphosphonic dichloride, which is conveniently assembled from the Diels-Alder reaction of cyclopentadiene and vinyl phosphonic dichloride. The OPC has been exploited in the rapid, efficient scavenging of primary and secondary amines that are present in excess following a common benzoylation event at room temperature (30-60 min) or under microwave conditions in shorter duration (<5 min).

Full text of DOI:10.1016/j.tetlet.2006.06.130

Tetrahedron Letters 47 (2006) 6429–6432
High-load, oligomeric phosphonyl dichloride: facile generation
via ROM polymerization and application to scavenging amines
a,b
a,b
c,
a,b,
*
*
Russell H. Herpel, Punitha Vedantham, Daniel L. Flynn and Paul R. Hanson
a
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, United States
b
The KU Chemical Methodology and Library Development Center of Excellence, 1501 Wakarusa Drive,
Lawrence, KS 66047, United States
c
Deciphera Pharmaceuticals LLC, 1505 Wakarusa, Drive, Lawrence, KS 66047, United States
Received 7 June 2006; revised 23 June 2006; accepted 23 June 2006
Abstract—A new ROMP-derived scavenging reagent, oligomeric phosphonyl dichloride (OPC), with high-load and selectivity is
reported. This reagent can be readily generated via the ROM polymerization of bicyclo[2.2.1]hept-5-en-2-ylphosphonic dichloride,
which is conveniently assembled from the Diels–Alder reaction of cyclopentadiene and vinyl phosphonic dichloride. The OPC has
been exploited in the rapid, efficient scavenging of primary and secondary amines that are present in excess following a common
benzoylation event at room temperature (30–60 min) or under microwave conditions in shorter duration (<5 min).
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
metathesis (ROM) polymerization has materialized as a
commanding platform to develop high-load, immobilized
4
,5
The growing demand for high throughput synthetic pro-
tocols has spurned efforts directed toward integrating
the sciences of organic synthesis and purification in order
to streamline drug discovery efforts. The emergence of
designer polymers with tunable properties has become a
powerful technological advancement in this arena of facil-
itated synthesis. A primary driver in this advance has been
the development of an array of polymer-bound reagents
reagents with tunable properties circumventing classi-
cal issues associated with conventional immobilized
reagents. To this end, we now report the synthesis and
utility of a high-load, oligomeric phosphonyl dichloride
using ROM polymerization.
Our interest in the development of purification protocols
based on norbornenyl reagents and ROMP strategies
has led us to recently communicate two novel scaveng-
ing approaches: (1) a chemical tagging scavenge-
1
,2
and scavengers, and corresponding technologies, which
effectively streamline synthetic methods to simple mix, fil-
ter, and evaporate protocols. The hallmark of these
3
6
ROMP-filter approach which utilized 5-norbornene-2-
methods is that they avoid the use of insoluble polymers
during the actual synthesis, yet retain the virtues of both
solution-phase and solid-phase approaches. While
substantial progress has been noted in this field, several
common restrictions encountered include reaction homo-
geneity (non-linear reaction kinetics), resin-load capacity,
and the method for reagent delivery. These prominent
issues continue to warrant the development of new poly-
mers for library production. Among these, ring-opening
methanol as a facile soluble electrophile scavenger that
is phase-trafficked out of solution via in situ ROM poly-
merization and (2) ROMP-scavenge-filter utilizing a
‘pre-formed,’ high-load, oligomeric sulfonyl chloride
7
(OSC) as an effective amine scavenger, and a higher-
8
load, oligomeric, bis-acid chloride (OBAC) that effec-
tively removes alcohols and thiols as well as amines from
a reaction mixture. In this report, we describe the gener-
ation of our highest load oligomer to-date, OPC, which
yields a theoretical load of 9.5 mmol/g.
Keywords: Phosphonyl dichloride; Ring-opening metathesis polymer-
ization (ROMP); High-load polymer; Insoluble polymer; Scavenging
agent; Supported reagents; Phosphonic dichloride.
2. Results and discussion
*
Corresponding authors. Tel.: +1 785 864 3094; fax: +1 785 864 5396
P.R.H.); e-mail: phanson@ku.edu
Our efforts to the titled high-load, ROMP-derived
phosphonyl dichloride (3, OPC) scavenging agent was
(
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.130

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R. H. Herpel et al. / Tetrahedron Letters 47 (2006) 6429–6432
initiated by the preparation of the phosphonyl dichlo-
ride monomer. The starting monomer, bicyclo[2.2.1]
hept-5-en-2-ylphosphonic dichloride (2), was produced
in a two-step sequence by first chlorination of vinylphos-
phonic acid (1) using oxalyl chloride and catalytic
DMF, followed by a Diels–Alder reaction between vinyl
phosphonic dichloride and cyclopentadiene in methyl-
ene chloride at 60 °C. Subsequent ROM polymerization
with either 6.7, 3.3, 2.0, or 1.0 mol % (IMesH )(PCy )
of 3 equiv of base11 and 2 equiv of amine. Subsequent
in situ scavenging of excess amine utilizing only
2
G
2.0 equiv of OPC100 was completed in 30–60 min at
TM
RT or 5 min at 100 °C in the microwave (Emrys Cre-
ator). The resulting mixture was diluted with EtOAc, fil-
1
2
tered thru a SPE, and concentrated under reduced
pressure to deliver the benzoylated amines 4a–l in excel-
1
3
lent yields and purities (Scheme 2).
2
3
9
(
Cl) Ru@CHPh (cat-B) yielded the corresponding
It was found that all OPCs efficiently removed both pri-
mary and secondary amines from a reaction mixture
after a benzoylation event. The only limitations of
amine scavenging noted are dibenzylamine and N-iso-
propylbenzylamine. Our justification for the aforemen-
tioned results may be due to the steric bulk of these
two molecules, in which bulky amines deter OPC from
reacting in both cases. However, dibenzylamine may
be scavenged with OPC by use of a microwave reactor
with extended heating of 10 min instead of 5 min as
necessary for the other amines investigated.
2
oligomers of 15, 30, 50, and 100 monomeric units
(
2
2
G
OPC15,30,50,100), respectively. Synthesis of 10,
1
G
0, and 30-mer ( OPC10,20,30) was also accomplished
using 10, 5, and 3.3 mol % (PCy ) (Cl) Ru@CHPh
3
2
2
1
0
(
cat-A). Quenching of the ROM polymerization event
was carried out with ethyl vinyl ether (EVE) in standard
fashion, followed by precipitation into a stirring
solution of Et O affording the desired oligomers as
2
free-flowing powders (Scheme 1).
We investigated the benzoylation of a variety of amines
present in excess (entries 1–12, Table 1) using the
Like its counterpart, OBAC, OPC contains two acid
chloride moieties that offer a substantial increase in
load. The theoretical load for OPC of 9.5 mmol/g
accounts for displacement of merely the two chloride
ligands. To our surprise we have found the actual load
to be 11.5–14 mmol/g. We have reported the load as a
range based on the following load studies: OPC was
added to known excess amounts of benzylamine and
2
G
solid OPC100 using either Et N or K CO as the base.
3
2
3
Simple amidation was accomplished in less than one
hour using 1 equiv of benzoyl chloride in the presence
O
1
. (COCl) , 55%
2
Cl
Cl
PO H
P
3
endo:exo
2
.
88%
1
2
.5:1
2
POCl2 (2 eq.)
6
.7, 3.3, 2.0,1.0 mol%
1
2
1
2
cat-B, CH Cl 40 °C
then EVE, (85-90%)
NHR R (2 eq.)
base (3 eq.)
scavenge
2
2
Bz-NR R (4)
1
2
Bz-NR R (4)
POCl2
BzCl
+
n
Pure
1
2
xs NHR R
or
3
POCl2
filter
OPC
9.5 mmol/g
1
0.0, 5.0, 3.3 mol%
2
GOPC1
5, 30, 50, 100
0, 20, 30
Scheme 2. Reagents and conditions: (i) Benzoylation: BzCl (1.0 equiv),
CH Cl , base (3.0 equiv), and amine (2.0 equiv) at rt (30 min); (ii)
cat-A, CH Cl 40 °C
then EVE, (85-90%)
2
2
1GOPC
1
2
2
scavenging: OPC 3 (2.0 equiv), CH
filter via SiO plug.
2
Cl
2
, 30–60 min at rt, then EtOAc,
Scheme 1.
2
2G
Table 1. Formation and isolation of pure benzoylated amines 4 using ROMP-scavenge-filter with OPC100
a
Entry
1
Amine
Conditions
Base
Et
Product
Yield (%)
Purity (%)
Benzylamine
A
B
A
A
A
B
A
A
B
3
N
4a
4a
4b
4c
4d
4d
4e
4f
93
>90
88
92
89
>90
97
95
>90
—
>90
89
>95
>95
>95
>95
>95
>95
>95
>95
>95
—
>95
>90
x
>90
>90
>95
K
2
CO
3
2
3
4
Octylamine
Phenethylamine
Diallylamine
Et
Et
Et
3
N
N
N
3
3
K
2
CO
3
5
6
Morpholine
Piperidine
Et
Et
3
N
N
3
K
2
CO
3
3
3
4f
7
Dibenzylamine
A
Et
3
N
4g
4g
4h
4i
b
B
K
2
CO
8
9
Ethanolamine
A
B
A
A
A
Et
3
N
N-Isopropylbenzylamine
n-Pentadecylamine
Diethanolamine
K
2
CO
x
10
11
12
Et
Et
Et
3
N
N
N
4j
98
94
96
3
3
4k
4l
Cyclohexylamine
2 2 2 2
Reagents and conditions: (A) rt, CH Cl (30–60 min). (B) MW, CH Cl (5 min at 100 °C).
a
1
Determined by GC and confirmed by H NMR (no polymer present, see supplementary spectra).
Microwave for 10 min at 100 °C.
b

R. H. Herpel et al. / Tetrahedron Letters 47 (2006) 6429–6432
6431
4
-methoxybenzylamine, respectively, with allylphenyl
Supplementary data
ether as an internal standard in the presence of Et N
3
1
4
in methylene chloride. The reaction was allowed to
proceed overnight to allow for complete saturation of
all reactive sites within OPC, and was then analyzed
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.06.130.
1
by H NMR spectroscopy to find the resultant amine
to ether ratio.
References and notes
We attribute this unexpected, extra load to H-bonding
of the amine with the oxygen atom of P@O. Several
experimental approaches were carried out to support
and explain this extremely high load. We believe that
formation of a phosphono-iminium species is not a
plausible explanation. This hypothesis is supported by
two simple experiments revealing only chloride displace-
ment when excess benzylamine was reacted with either
norbornene phosphonic dichloride or methyl phospho-
nic dichloride.
1
. (a) Booth, R. J.; Hodges, J. C. Acc. Chem. Res. 1999, 32,
18–26; (b) Ley, S. V.; Baxendale, I. R.; Bream, R. N.;
Jackson, P. S.; Leach, A. G.; Longbottom, D. A.; Nesi,
M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J. Chem. Soc.,
Perkin Trans. 1 2000, 3815–4195; (c) Kirschning, A.;
Monenschein, H.; Wittenberg, R. Angew. Chem., Int. Ed.
2
001, 40, 650–679; (d) Eames, J.; Watkinson, M. Eur. J.
Org. Chem. 2001, 1213–1224.
2
. For use of soluble polymers, see: (a) Dickerson, T. J.;
Reed, N. N.; Janda, K. D. Chem. Rev. 2002, 102, 3325; (b)
Haag, R. Chem. Eur. J. 2001, 7, 327; (c) Haag, R.; Sunder,
A.; Hebel, A.; Roller, S. J. Comb. Chem. 2002, 4, 112; (d)
Bergbreiter, D. E. Chem. Rev. 2002, 102, 3345.
3. For an excellent review on polymer-assisted solution-
phase (PASP) protocols, see: Parlow, J. J. Curr. Opin.
Drug Discovery Develop. 2005, 8, 757–775.
. (a) Barrett, A. G. M.; Hopkins, B. T.; K o¨ bberling, J.
Chem. Rev. 2002, 102, 3301–3324; (b) Flynn, D. L.;
Hanson, P. R.; Berk, S. C.; Makara, G. M. Curr. Opin.
Drug Discovery Develop. 2002, 5, 571–579; (c) Harned, A.
M.; Probst, D. A.; Hanson, P. R. The use of olefin
metathesis in combinatorial chemistry: supported and
chromatography-free syntheses. In Handbook of Metath-
esis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003;
Vol. 2, pp 361–402.
5. (a) Harned, A. M.; Zhang, M.; Vedantham, P.; Mukher-
jee, S.; Herpel, R. H.; Flynn, D. L.; Hanson, P. R.
Aldrichim. Acta 2005, 38, 3–16; (b) Barrett, A. G. M.;
Bibal, B.; Hopkins, B. T.; Koebberling, J.; Love, A. C.;
Tedeschi, L. Tetrahedron 2005, 61, 12033–12041; (c)
Fuchter, M. J.; Hoffman, B. M.; Barrett, A. G. M. J.
Org. Chem. 2005, 70, 5086–5091; (d) Harned, A. M.;
Sherrill, W. M.; Flynn, D. L.; Hanson, P. R. Tetrahedron
Unlike OBAC that was found to bond with alcohols,
amines and thiols, OPC has the ability to selectively
bond with amines. Similar benzoylation reactions as
previously discussed with amines were attempted with
benzyl alcohol, phenol, and n-butanethiol, in which
the OPC was unable to scavenge the excess reagent in
each case. To further support this selectivity concept,
benzoylation of ethanolamine and diethanolamine
4
(
entries 8 and 11) result in the formation of amide bonds
with free 1° OH group(s). Also, a competition reaction
was set up with both benzyl alcohol and benzylamine
in the presence of OPC and the expected conclusion of
OPC reacting solely with benzylamine was observed.
This notable selectivity for amines could potentially be
quite advantageous in library synthesis as a simple
method for removal of excess amines in the presence
of other functional groups.
3. Conclusions
2
005, 61, 12093–12099.
Overall, several high-load, OPC scavengers have been
conveniently prepared on large scale from inexpensive
and readily available starting materials. These scaveng-
ing reagents offer high-load benefits, exceptional selec-
tivity for bonding with primary and secondary amines,
and simple removal by silica gel SPE. Additional use
in other transformations is underway and will be re-
ported in due course.
6. Moore, J. D.; Harned, A. M.; Henle, J.; Flynn, D. L.;
Hanson, P. R. Org. Lett. 2002, 4, 1847–1849.
7. Moore, J. D.; Herpel, R. H.; Lichtsinn, J. R.; Flynn, D. L.;
Hanson, P. R. Org. Lett. 2003, 5, 105–107.
8
. Moore, J. D.; Byrne, R. J.; Vedantham, P.; Flynn, D. L.;
Hanson, P. R. Org. Lett. 2003, 5, 4241–4244.
9
. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1
999, 1, 953–956.
1
0. The size of the polymer is calculated using the following
equation: length = 100/(mol % catalyst). It is important to
note that these oligomers are generated as a Gaussian
distribution with the most heavily populated region
corresponding to the size calculated from this equation.
Acknowledgements
This investigation was generously supported by partial
funds provided by the University of Kansas Research
Development Fund, the National Institutes of Health
11. It is worthy to note that excess base is readily removed by
either concentration under reduced pressure (Et N) or
3
filtration (K
2
3
CO ).
1
2. When using K
2
CO as the base, no filtration through
3
(
KU Chemical Methodologies and Library Develop-
SiO2 is necessary, as final products of high purity can
be obtained using only precipitation/filtration. However
ment Center of Excellence, P50 GM069663), and NIH
COBRE award P20 RR015563 with additional funds
from the State of Kansas. The authors thank Materia,
Inc. for supplying catalyst and helpful discussions. The
authors would also like to acknowledge the intellectual
efforts provided by Matthew McReynolds and Mianji
Zhang.
in the cases of Et N, a small contaminant of amine salt
3
1
is evident from H NMR analysis. We have found
that using a small pad of SiO as a filter aid can remedy
2
this problem.
1
13. H NMR spectra of all crude products are available in the
Supplementary data.

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R. H. Herpel et al. / Tetrahedron Letters 47 (2006) 6429–6432
1
4. The theoretical load of this polymer is calculated at
.5 mmol/g. The actual load was experimentally deter-
measure the uptake of benzyl amine by OPC in refluxing
CH Cl using allyl phenyl ether as an internal standard
and Et N as a base.
9
2
2
1
mined to be 11.5–14.0 mmol/g utilizing H NMR to
3