High-Load, ROMP-Generated Oligomeric Bis-acid Chlorides: Design of Soluble and Insoluble Nucleophile Scavengers

Article abstract of DOI:10.1021/ol0352759

(Equation presented) An efficient strategy for scavenging a host of nucleophiles utilizing an oligomeric bis-acid chloride (OBAC), generated from the ROM polymerization of trans-bicyclo[2.2.1]hept-5-ene-2,3-dicarbonyl dichloride, is described. The reactivity and high load of the OBAC reagent is exploited in the scavenging of amines, alcohols, and thiols that are present in excess following a common benzoylation event. Following the scavenging event, these oligomers can be precipitated with EtOAc and filtered (SiO₂), leaving benzoylated nucleophiles in excellent yield and purity.

Full text of DOI:10.1021/ol0352759

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4241-4244
High-Load, ROMP-Generated Oligomeric
Bis-acid Chlorides: Design of Soluble
and Insoluble Nucleophile Scavengers
,‡
Joel D. Moore,† Robert J. Byrne,† Punitha Vedantham,† Daniel L. Flynn,* and
,†
Paul R. Hanson*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045-7582, and Neogenesis, 840 Memorial DriVe,
Cambridge, Massachusetts 02139
phanson@ku.edu
Received July 10, 2003
ABSTRACT
An efficient strategy for scavenging a host of nucleophiles utilizing an oligomeric bis-acid chloride (OBAC), generated from the ROM polymerization
of trans-bicyclo[2.2.1]hept-5-ene-2,3-dicarbonyl dichloride, is described. The reactivity and high load of the OBAC reagent is exploited in the
scavenging of amines, alcohols, and thiols that are present in excess following a common benzoylation event. Following the scavenging
event, these oligomers can be precipitated with EtOAc and filtered (SiO ), leaving benzoylated nucleophiles in excellent yield and purity.
2
The emergence of combinatorial chemistry over the past
decade1 has brought about several technological advances
in the area of impurity removal.2-4 Among these, scavenger
resins5 have emerged as powerful tools that avoid the use of
insoluble polymers during the synthesis event yet retain the
virtues of both solution-phase and solid-phase approaches.
Despite these advances, limitations in both nonlinear reaction
kinetics and low-load parameters warrant the continued
development of new designer polymers in this area. Two
common methods have surfaced to address these issues: (1)
chemical tagging6 and (2) the use of soluble, polymeric
supports, reagents, and scavenging agents.7-10 Regarding the
latter strategy, PEG-based soluble polymers are the most
prevalent.7 Recently, however, a number of alternative
systems have emerged, including several dendritic9 and
polyacrylamide7 systems and a variety of ROMP-derived
polymers pioneered by Barrett and co-workers.11 In all of
these systems, it is of paramount importance to develop new
† University of Kansas.
‡ Neogenesis. Currently at Deciphera Pharmaceuticals, Inc. E-mail:
dflynn@deciphera.com.
(1) (a) A Practical Guide to Combinatorial Chemistry; Czarnik, A. W.,
DeWitt, S. H., Eds.; American Chemical Society: Washington, DC, 1997.
(b) Bunin, B. A. The Combinatorial Index; Academic Press: New York,
1998. (c) Combinatorial Chemistry: A Practical Approach; Fenniri, H.,
Ed.; The Practical Approach Series 233; Oxford University Press: New
York, 2000.
(2) Reviews: (a) 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. (b) Hall,
D. G.; Manku, S.; Wang, F. J. Comb. Chem. 2001, 3, 125-150.
(3) Review: Guillier, F.; Orain, D.; Bradley, M. Chem. ReV. 2000, 100,
2091-2157.
(5) (a) Kaldor, S. W.; Fritz, J. E.; Tang, J.; McKinney, E. R. Biorg. Med.
Chem. Lett. 1996, 6, 3041-3044. (b) Kaldor, S. W.; Siegel, M. G.; Fritz,
J. E.; Dressman, B. A. Hahn, P. J. Tetrahedron Lett. 1996, 37, 7193-
7196. (c) 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, 4874-4881.
(d) Booth, R. J.; Hodges, J. C. J. Am. Chem. Soc. 1997, 119, 4882-4886.
Reviews: (e) Booth, R. J.; Hodges, J. C. Acc. Chem. Res. 1999, 32, 18-
26. (f) Eames, J.; Watkinson, M. Eur. J. Org. Chem. 2001, 1213-1224.
(4) Review: Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis
1997, 1217-1239.
10.1021/ol0352759 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/23/2003

soluble, polymeric scaffolds with vast differential solubility
profiles12 in order to optimize facile phase-trafficking
protocols.
89 or 40 mg/mL CH2Cl2 solution17 (40-mer, generated from
the first-generation Grubbs catalyst, 1GOBAC40). Details of
the polymer design are outlined below.
Our interest in the development of purification protocols
based on norbornenyl reagents13 and ROMP strategies11,14
has led us to recently communicate two novel scavenging
approaches: (1) a chemical tagging scavenge-ROMP-filter
approach14 that utilizes 5-norbornene-2-methanol as a facile
soluble electrophile scavenger that is phase-trafficked out
of solution via in situ ROM polymerization and (2) ROMP-
scavenge-filter utilizing a “preformed”, high-load, oligo-
meric sulfonyl chloride (OSC) as an effective amine scav-
enger.15 We are now reporting a powerful extension to these
methods that utilizes a high-load, oligomeric, bis-acid
chloride (OBAC) as a general nucleophile scavenger. Unlike
its sulfonyl chloride predecessor, this oligomer can now
effectively remove alcohols and thiols as well as amines from
a reaction mixture. Also, because each monomer unit
contains two acid chloride moieties, the OBAC reagent offers
a significant increase in load. Like the OSC, this system
offers flexible oligomer design and compatibility with
traditional reaction monitoring methods. In addition, the
OBAC reagent has a wide solubility profile that allows
precipitation/filtering from EtOAc as the sole purification
protocol.
The requisite monomer, trans-bicyclo[2.2.1]hept-5-ene-
2,3-dicarbonyl dichloride (1), is produced in a two-step
sequence beginning with a Diels-Alder reaction between
fumaric acid and cyclopentadiene in 10:1 acetone/water at
50 °C followed by chlorination using oxalyl chloride and
catalytic DMF. Subsequent ROM polymerization with either
1 mol % (IMesH2)(PCy3)(Cl)2RudCHPh (second-generation
Grubbs catalyst, 4)18 or 2.5 mol % (PCy3)2(Cl)2RudCHPh
(first-generation Grubbs catalyst, 3) yields the 100-mer (2a)
or 40-mer (2b) OBAC reagent, respectively.19 Quenching
of the ROM polymerization is carried out in standard fashion
with ethyl vinyl ether. The length of the oligomer, in
Scheme 1
The OBAC reagent can be introduced into the reaction
system as an insoluble solid (100-mer, generated using the
16
second-generation Grubbs catalyst, 2GOBAC100
)
or as an
(6) (a) Curran, D. P.; Hadida, S. J. Am. Chem. Soc. 1996, 118, 2531-
2532. (b) Flynn, D. L.; Devraj, R. V.; Naing, W.; Parlow, J. J.; Weidner,
J. J.; Yang, S. Med. Chem. Res. 1998, 8, 219-243. (c) Parlow, J. J.; Naing,
W.; South, M. S.; Flynn, D. L. Tetrahedron Lett. 1997, 38, 7959-7962.
(d) Starkey, G. W.; Parlow, J. J.; Flynn, D. L. Bioorg. Med. Chem. Lett.
1998, 8, 2385-2390. (e) Luo, Z.; Zhang, Q.; Oderaotoshi, Y.; Curran, D.
P. Science 2001, 291, 1766-1769. (f) Zhang, W.; Luo, Z.; Chen, C. H.-T.;
Curran, D. P. J. Am. Chem. Soc. 2002, 124, 10443-10450. (g) Bosanac,
T.; Yang, J.; Wilcox, C. S. Angew. Chem., Int. Ed. 2001, 40, 1875-1879.
(h) Bosanac, T.; Wilcox, C. S. J. Am. Chem. Soc. 2002, 124, 4194-4195.
(i) Ley, S. V.; Massi, A.; Rodriguez, F.; Harwell, D. C.; Lewthwaite, R.
A.; Pritchard, M. C.; Reid, A. M. Angew. Chem., Int. Ed. 2001, 40, 1053-
1055.
(7) Review: (a) Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. ReV.
2002, 102, 3325-3343. (b) Gravert, D. J.; Janda, K. D. Chem. ReV. 1997,
97, 489-509. (c) Toy, P. H.; Janda, K. D. Acc. Chem. Res. 2000, 33, 546-
554. (d) Bergbreiter, D. E. Chem. ReV. 2002, 102, 3345-3384.
(8) For use of ROM polymers as organic soluble supports for radical
reactions, see: (a) Enholm, E. J.; Gallagher, M. E. Org. Lett. 2001, 3, 3397-
3399. (b) Enholm, E. J.; Cottone, J. S. Org. Lett. 2001, 3, 3959-3962.
ROM polymers as soluble catalysts: (c) Bolm, C.; Dinter, C. L.; Seger,
A.; Ho¨cker, H.; Brozio, J. J. Org. Chem. 1999, 64, 5730-5731.
(9) (a) Haag, R. Chem. Eur. J. 2001, 7, 327-335. (b) Haag, R.; Sunder,
A.; Hebel, A.; Roller, S. J. Comb. Chem. 2002, 4, 112-119.
(10) Falchi, A.; Taddei, M. Org. Lett. 2000, 2, 3429-3431.
(11) (a) Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.; Zecri, F. J.
Org. Lett. 1999, 1, 579-582. (b) Barrett, A. G. M.; Hopkins, B. T.;
Ko¨bberling, J. Chem. ReV. 2002, 102, 3301-3323 and references therein.
(12) Gravert, D. J.; Datta, A.; Wentworth, P., Jr.; Janda, K. D. J. Am.
Chem. Soc. 1998, 120, 9481-9485.
conjunction with its method of formation, is crucial with
respect to reagent solubility. We have found that the OBAC
reagent is an effective scavenger when added as a solid or
as a solution. Using 1 mol % catalyst 4 generates the 100-
mer that can be isolated and readily used as a heterogeneous,
solid nucleophile scavenger (2GOBAC100). We also wished
to demonstrate the effectiveness of adding the oligomer as
a homogeneous solution; therefore, we carried out the
polymerization event using 2.5 mol % catalyst 3, generating
the more soluble 40-mer (1GOBAC40). This oligomer could
be readily dissolved in CH2Cl2 and used as either an 89 or
40 mg/mL stock scavenger solution. Interestingly, when
catalyst 4 (second-generation) was used in the production
of the 40-mer, it was found that the polymer would not go
completely back into solution following precipitation. We
believe that this can be partially attributed to the difference
in shape (E/Z ratio of polymer backbone) of the two
oligomers that occurs when changing from one catalyst to
the other.13b
We initially investigated the benzoylation of a variety of
amines present in excess (entries 1-12, Table 1) using the
(13) For the first example of a norbornenyl-tagged reagent, see: (a)
Barrett, A. G. M.; Roberts, R. S.; Schro¨der, J. Org. Lett. 2000, 2, 2999-
3001. (b) For the use of a capture-ROMP-release, see: Harned, A. M.;
Hanson, P. R. Org. Lett. 2002, 4, 1007-1010.
(14) Moore, J. D.; Harned, A. M.; Henle, J.; Flynn, D. L.; Hanson, P.
R. Org. Lett. 2002, 4, 1847-1849.
(15) Moore, J. D.; Herpel, R. H.; Lichtsinn, J. R.; Flynn, D. L.; Hanson,
P. R. Org. Lett. 2003, 5, 105-107.
(17) It was discovered that the 89 mg/mL stock solution would “gel”
upon cooling over a 48 h period. However, simple dilution to a 40 mg/mL
stock solution readily overcame this problem. Both solutions scavenged
nucleophiles with equal effectiveness.
(18) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(16) Oligomeric bis-acid chloride reagent is abbreviated according to
the “generation” of Grubbs catalyst used for the polymerization (the
superscript before the OBAC) and the length of polymer (the subscript
following the OBAC acronym).
(19) 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.
4242
Org. Lett., Vol. 5, No. 23, 2003

scavenger was unable to effectively scavenge alcohols
presumably due to the generation of a labile sulfonate ester.
Although higher temperatures and 2 equiv of the scavenger
were required for efficient scavenging (refluxing DCM,
∼1-2 h), we were pleased to find that a wide scope of
alcohols could be scavenged, including allylic, propargylic,
and secondary alcohols (Table 2).
Table 1. Formation and Isolation of Pure of Benzoylated
Amines 5 Using ROMP-Scavenge-Filter with 2GOBAC100
entry
amineb
base
Et3N
K2CO3
pdt yield (%) purity (%)a
1
2
3
4
5
6
7
8
9
benzylamine
benzylamine
benzylamine
n-octylamine
morpholine
phenethylamine
phenethylamine
cyclohexylamine
cyclohexylamine
methylbenzylamine Et3N
dibenzylamine
diallylamine
5a
5a
99
93
94
98
95
83
96
93
99
97
99
97
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
Cs2CO3 5a
Et3N
Et3N
Et3N
pyridine 5d
Et3N 5e
pyridine 5e
5b
5c
5d
Table 2. Formation of Benzoylated Alcohols 6 Using
ROMP-Scavenge-Filter with 2GOBAC100
entry
alcoholb
pdt
yield (%)
purity (%)a
10
11
12
5f
5g
5h
1
2
3
4
5
6
7
8
benzyl alcohol
2-allyloxy ethanol
4-MeO-benzyl alcohol
geraniol
propargyl alcohol
2-octanol
6a
6b
6c
6d
6e
6f
94
99
91
94
99
40
78
46
>95
>95
>95
>95
>95
>95
>95
>95
Et3N
Et3N
1
a Determined by GC and confirmed by H NMR (no polymer present;
see supplementary spectra in Supporting Information).
3-Me-2-butene-1-ol
(-)-menthol
6g
6h
solid 2GOBAC100 and a variety of bases. Facile amidation
was accomplished in less than 1 h using 1 equiv of benzoyl
chloride in the presence of 5 equiv of base20 and 2 equiv of
amine. Subsequent in situ scavenging of excess amine
utilizing only 1.0 equiv21 of 2GOBAC100 2a was completed
within 30 min. The resulting mixture was diluted with
EtOAc, filtered (SiO2),22 and concentrated under reduced
pressure to yield the benzoylated amines 5a-h in excellent
yields and purities.23 Following this success, we then
1
a Determined by GC and confirmed by H NMR (no polymer present;
see supplementary spectra in Supporting Information).
As a final extension to this work, we investigated the
scavenging of thiol nucleophiles. Again, we were pleased
to find that 2 equiv of 2GOBAC100 could scavenge thiols from
a reaction mixture (Table 3).
Scheme 2a
Table 3. Formation and Isolation of Pure of Benzoylated
Thiols 7a Using ROMP-Scavenge-Filter with 2GOBAC100
entry
thiol
pdt
yield (%)
purity (%)a
1
2
3
methyl thioglycolate
butane thiol
1-dodecane thiol
7a
7b
7c
83
86
99
>95
>95
>95
1
a Determined by GC and confirmed by H NMR (no polymer present;
a Reagents and conditions: (i) Benzoylation: BzCl (1.0 equiv),
CH2Cl2, base (5.0 equiv), and amine (2.0 equiv) at rt (20 min). (ii)
Scavenging: OBAC 2 (1.0 equiv), CH2Cl2, 30 min at rt, then
EtOAc, filter via SiO2 plug.
see supplementary spectra in Supporting Information).
We next directed our efforts at the development of
a soluble version of the bis-acid chloride oligomer. Fol-
lowing an extensive investigation, it was found that a 40-
mer generated with the first-generation Grubbs catalyst
(1GOBAC40) was ideal. We therefore prepared a stock
solution of the 1GOBAC40 reagent in DCM (88 or 40 mg/
mL stock solution) and studied its reactivity against a panel
of amines, alcohols, and thiols.17 We were pleased to find
that the 1GOBAC40 was also extremely effective in scaveng-
ing all of the substrates outlined in Table 4.
investigated the possibility of alcohol scavenging utilizing
the 2GOBAC100 reagent. Our previously reported OSC
(20) It is noteworthy that excess base is readily removed by either
concentration under reduced pressure (Et3N, pyridine) or filtration (K2CO3,
Cs2CO3).
(21) Equivalents in this context refer to molar equivalents and not load,
which we have measured, vide infra. The load value measured in mmols/
gram incorporates the mmols of reactive functional groups/gram of polymer
(see footnote 25). The weight of polymer used, based on molar equivalents,
was determined using the molecular weight of the monomeric bis-acid
chloride starting unit.
To further assess the synthetic utility of the OBAC
scavengers, it was deemed necessary to compare the ef-
fectiveness of the OBACs as general nucleophile scavengers
versus a commercially available counterpart. Since bis-acid
chloride resins are not commercially available, we chose to
compare the titled OBAC scavengers with commercially
available, polystyrene-based isocyanate resins commonly
(22) When using K2CO3 or Cs2CO3 as the base, no filtration through
SiO2 is necessary, as final products of high purity can be obtained using
only precipitation/filtration. However, in the cases of Et3N and pyridine, a
small contaminant of amine salt is evident from 1H NMR analysis. We
have found that using a small pad of SiO2 as a filter aid can remedy this
problem.
(23) 1H NMR spectra of all crude products are available in Supporting
Information.
Org. Lett., Vol. 5, No. 23, 2003
4243

the case of benzyl alcohol.26 In this latter example, it was
seen that after 2 h, the OBAC reagents had sufficiently
scavenged all the alcohol present, while the reaction contain-
ing the commercially available isocyanate scavenger resin
still possessed 20% of the starting alcohol.
Table 4. Scavenging with a Solution of 1GOBAC40
entry
nucleophile
base
pdt yield (%) puritya (%)
1
2
3
4
5
6
7
8
9
benzylamine
n-octylamine
morpholine
phenethylamine
diallylamine
diallylamine
methylbenzylamine Cs2CO3 5f
benzyl alcohol
3-Me-2-butene-1-ol
methyl thioglycolate Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
5a
5b
5c
5d
5h
99
99
94
85
98
95
99
95
99
99
>95
>95
>95
>95
>95
87
In conclusion, we have developed high-load, bis-acid
chloride oligomers that serve as effective heterogeneous and
homogeneous nucleophile scavengers that can be introduced
into the reaction system as a solid (100-mer) or as a stock
solution (40-mer). In addition, the use of only a single
equivalent of excess scavenging agent, in combination with
the expedient manner (<30 min to 2 h) in which the
scavenging event occurs, demonstrates the enormous poten-
tial of this new method in combinatorial chemistry. The
utilization of OBAC reagents in the area of combinatorial
library development and organic synthesis is currently under
investigation and will be reported in due course.
K2CO3 5h
95
Et3N
Et3N
6a
6g
7a
>95
>95
>95
10
1
a Determined by GC and confirmed by H NMR (no polymer present;
see supplementary spectra in Supporting Information).
used in organic synthesis.24 One clear advantage quickly
becomes apparent and pertains to the “load” of the OBAC
scavengers, which is higher than the corresponding isocy-
anate polystyrene resin (8.3 mmol/g25 vs ∼1.3 mmol/g).
Thus, the amount of OBAC reagent required for each
scavenging reaction is 6.5 times lower than the amount of
isocyanate resin for a given experimental procedure. In a
typical comparison experiment, we employed 35 mg of
OBAC to 250 mg of the polystyrene-based isocyanate.
In addition, both 1GOBAC40 and the 2GOBAC100 scavengers
performed similarly (yields and reaction times) to the
commercially available isocyanate reagent in the cases of
benzylamine and methyl thioglycolate and slightly better in
Acknowledgment. This investigation was generously
supported by partial funds provided by the National Science
Foundation (NSF Career 9984926), the National Institutes
of Health (National Institute of General Medical Sciences,
RO1-GM58103), and the National Institutes of Health
COBRE award 1 P20 RR15563, with matching support from
the State of Kansas, and the University of Kansas. The
authors also thank Materia, Inc., for many helpful discus-
sions.
Supporting Information Available: Detailed experi-
1
mental procedures and H NMR spectra of crude products
(24) (a) Creswell, M. W.; Bolton, G. L.; Hodges, J. C.; Meppen, M.
Tetrahedron 1998, 54, 3983-3998. (b) Booth, J. R.; Hodges, J. C. J. Am.
Chem. Soc. 1997, 119, 4882-4886. (c) Rebek, J.; Brown, D.; Zimmerman,
S. J. Am. Chem. Soc. 1975, 97, 4407-4408. Exact details of these
competition experiments can be found in Supporting Information.
(25) The theoretical load of this polymer is calculated at 9.1 mmol/g.
The actual load was experimentally determined to be 8.1-8.5 mmol/g
utilizing 1H NMR to measure the uptake of benzyl amine by OBAC in
refluxing deuterated DCM using allyl phenyl ether as an internal standard
and Et3N as a base. Room temperature uptake was measured at 7 mmol/g.
obtained by the OBAC ROMP-scavenge-filter method.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0352759
(26) Exact details of these competition experiments can be found in
Supporting Information.
4244
Org. Lett., Vol. 5, No. 23, 2003