Scavenge-ROMP-filter: a facile strategy for soluble scavenging via norbornenyl tagging of electrophilic Reagents.

Article abstract of DOI:10.1021/ol0257880

[reaction: see text] A new "chemical tagging" method for homogeneous electrophilic scavenging is described. The method utilizes 5-norbornene-2-methanol to scavenge/tag a variety of electrophiles that are present in excess. Once tagging is complete, the crude reaction mixture is subjected to a rapid ROM polymerization event utilizing the second generation Grubbs catalyst. This process yields a polymer that can be precipitated with methanol or ether/hexane, leaving products in excellent yield and purity.

Full text of DOI:10.1021/ol0257880

ORGANIC
LETTERS
2002
Vol. 4, No. 11
1847-1849
Scavenge−ROMP−Filter: A Facile
Strategy for Soluble Scavenging via
Norbornenyl Tagging of Electrophilic
Reagents
,‡
Joel D. Moore,† Andrew M. Harned,† Julia Henle,§ Daniel L. Flynn,* and
,†
Paul R. Hanson*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045-7582, and Neogenesis Pharmaceuticals, Inc.,
840 Memorial DriVe, Cambridge, Massachusetts 02139
phanson@ku.edu
Received February 27, 2002
ABSTRACT
A new “chemical tagging” method for homogeneous electrophilic scavenging is described. The method utilizes 5-norbornene-2-methanol to
scavenge/tag a variety of electrophiles that are present in excess. Once tagging is complete, the crude reaction mixture is subjected to a rapid
ROM polymerization event utilizing the second generation Grubbs catalyst. This process yields a polymer that can be precipitated with methanol
or ether/hexane, leaving products in excellent yield and purity.
The development of new technologies to eliminate or lessen
the need for chromatographic separation of mixtures is of
continued interest in the field of synthetic organic chemistry1
and combinatorial chemistry.2 To facilitate impurity removal/
product purification, several strategies can be employed,
including solid polymer supports3 and reagents,4 organic
soluble supports and reagents,5 and scavenger resins.6 The
use of scavenger resins for purification avoids the use of
polymers during the actual synthesis and thus offers the
convenience of solution phase with the luxuries of solid
phase. Limitations to these scavenging resins include sluggish
reaction kinetics for removal of solution-phase reactants due
to the heterogeneous reaction environment and the limited
† University of Kansas.
‡ Neogenesis: dflynn@neogenesis.com
§ Undergraduate exchange student. Institut fu¨r Organische Chemie,
Universita¨t Regensburg.
(4) Review: Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis
1997, 1217-1239.
(1) 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.
(2) (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.
(5) Reviews: (a) Gravert, D. J.; Janda, K. D. Chem. ReV. 1997, 97, 489-
509. (b) Toy, P. H.; Janda, K. D. Acc. Chem. Res. 2000, 33, 546-554. (c)
For use of ROM polymers as organic soluble supports for radical reactions,
see: (d) Enholm, E. J.; Gallagher, M. E. Org. Lett. 2001, 3, 3397-3399.
(e) Enholm, E. J.; Cottone, J. S. Org. Lett. 2001, 3, 3959-3962. ROM
polymers as soluble catalysts: (f) Bolm, C.; Dinter, C. L.; Seger, A.; Ho¨cker,
H.; Brozio, J. J. Org. Chem. 1999, 64, 5730-5731.
(6) (a) Flynn, D. L.; Crich, J. Z.; Devraj, R. V.; Hockerman, S. L.; Parlow,
J. J.; South, M. S.; Woodard, S. J. Am. Chem. Soc. 1997, 119, 4874-4881.
(b) Booth, R. J.; Hodges, J. C. J. Am. Chem. Soc. 1997, 119, 4882-4886.
Reviews: (c) Booth, R. J.; Hodges, J. C. Acc. Chem. Res. 1999, 32, 18-
26. (d) Eames, J.; Watkinson, M. Eur. J. Org. Chem. 2001, 1213-1224.
(3) Review: Guillier, F.; Orain, D.; Bradley, M. Chem. ReV. 2000, 100,
2091-2157.
10.1021/ol0257880 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/27/2002

loading capacity (mmol functionality per g of resin) of
commonly used scavenging resins.
Scheme 1a
To overcome these limitations, chemical tagging has
recently been employed to facilitate impurity removal.7 The
hallmark of this approach is the inherent ability of a chemical
tag to phase-switch or phase-traffic reagents, products, and
impurities from one media to another due to the unique
“functionality” that is contained in the tag, thus enabling
efficient purification. The salient feature that differentiates
“chemical tagging” from supported synthesis/reagents is that
the reactivity of the reagent is not altered or compromised
in the process. Successful examples in this class include
fluorous tags,8 sequestration enabling reagents,6a,9 precipi-
tons,10 metal-chelated tagging,11 PEG tags for soluble-
supported scavenging,12 and Barrett’s norbornenyl-tagged
annihilation reagent.13
Recently, Barrett has taken a ring-opening metathesis
polymerization (ROMP) approach to impurity removal with
the development of ROMPgel technology14 utilizing the
Grubbs benzylidene catalyst [(PCy3)2(Cl)2RudCHPh]. Our
interest in the development of purification protocols based
on tagged reagents9 and ROMP15 has led us to develop a
new chemical tagging approach that we have termed
scavenge-ROMP-filter. This new method utilizes 5-nor-
bornene-2-methanol (1)16 as a soluble electrophilic scavenger.
This method offers maximum load benefits, is compatible
with traditional reaction monitoring methods, and retains the
favorable reaction kinetics associated with solution-phase
synthesis.
a Reagents and conditions: method A, (i) TsNCO, CH2Cl2, 0
°C to rt, then 1, 0 °C to rt, (ii) 1 mol % of 11, CH2Cl2, reflux
(20-45 min), (iii) Et2O/hexane (4:1), filter; method B, (i) PhNCO,
toluene, reflux, then 1, reflux, (ii) 1 mol % of 11, CH2Cl2, reflux
(20-45 min), (iii) MeOH, filter thru Celite; method C, (i) PhCOCl,
Et3N, CH2Cl2, rt or reflux, then 1, reflux, (ii) 1 mol % of 11, CH2Cl2,
reflux (20-45 min), (iii) Et2O/hexane (4:1), filter thru Celite or
SiO2 plug.
p-toluenesulfonyl isocyanate, phenyl isocyanate, and benzoyl
chloride. Subsequent in situ ROM polymerization using 1
mol % of the Grubbs saturated imidazole catalyst (IMesH2)-
(PCy3)(Cl)2RudCHPh (11)17 generates differentially soluble
polymers18 8-10 containing the tagged electrophiles 5-7.
The products 2-4 (Table 1) are readily isolated in solution
phase away from the in situ polymerized species 8-10 via
As shown in Scheme 1, the soluble scavenging alcohol 1
is utilized to capture excess electrophilic reagents such as
(7) Flynn, D. L.; Devraj, R. V.; Naing, W.; Parlow, J. J.; Weidner, J. J.;
Yang, S. Med. Chem. Res. 1998, 8, 219-243.
(8) (a) Curran, D. P.; Hadida, S. J. Am. Chem. Soc. 1996, 118, 2531-
2532. (b) Studer, A.; Curran, D. P. Tetrahedron 1997, 53, 6681-6696. (c)
Curran, D. P. Med. Res. ReV. 1999, 19, 432-438. (d) Curran, D. P. Synlett
2001, 1488-1496.
Table 1. Formation of Products 2-4a via
Scavenge-ROMP-Filterb
entry
nucleophile
electrophilea pdt yield (%) purity (%)
(9) (a) Parlow, J. J.; Naing, W.; South, M. S.; Flynn, D. L. Tetrahedron
Lett. 1997, 38, 7959-7962. (b) Starkey, G. W.; Parlow, J. J.; Flynn, D. L.
Bioorg. Med. Chem. Lett. 1998, 8, 2385-2390.
1
2
3
t-BuOH
BnOH
BnNH2
C6H11NH2
TolSO2NCO 2a
TolSO2NCO 2b
TolSO2NCO 2c
TolSO2NCO 2d
98
94
99
97
99
90
99
78
99
99
99
99
99
99
94
98
99
99
>90c
>90c
>90c
>90c
>90c
>90c
97d
(10) (a) Bosanac, T.; Wilcox, C. S. Chem. Commun. 2001, 1618-1619.
(b) Bosanac, T.; Wilcox, C. S. Tetrahedron Lett. 2001, 42, 4309-4312.
(c) Bosanac, T.; Yang, J.; Wilcox, C. S. Angew. Chem., Int. Ed. 2001, 40,
1875-1879. (d) Bosanac, T.; Wilcox, C. S. J. Am. Chem. Soc. 2002, 124,
4194-4195.
(11) Ley, S. V.; Massi, A.; Rodriguez, F.; Horwell, D. C.; Lewthwaite,
R. A.; Pritchard, M. C.; Reid, A. M. Angew. Chem., Int. Ed. 2001, 40,
1053-1055.
(12) Falchi, A.; Taddei, M. Org. Lett. 2000, 2, 3429-3431.
(13) (a) Barrett, A. G. M.; Roberts, R. S.; Schro¨der, J. Org. Lett. 2000,
2, 2999-3001. (b) For the initial paper on impurity annihilation, see:
Barrett, A. G. M.; Smith, M. L.; Zecri, F. J. Chem. Commun. 1998, 2317-
2318.
(14) (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.; Cramp, S. M.; Roberts,
R. S.; Zecri, F. J. Org. Lett. 2000, 2, 261-264. (c) Arnauld, T.; Barrett, A.
G. M.; Cramp, S. M.; Roberts, R. S.; Ze´cri, F. J. Org. Lett. 2000, 2, 2663-
2666. (d) Barrett, A. G. M.; Cramp, S. M.; Hennessy, A. J.; Procopiou, P.
A.; Roberts, R. S. Org. Lett. 2001, 3, 271-273. (e) Arnauld, T.; Barrett,
A. G. M.; Seifried, R. Tetrahedron Lett. 2001, 42, 7899-7901. (f) Arnauld,
T.; Barrett, A. G. M.; Hopkins, B. T.; Ze´cri, F. J. Tetrahedron Lett. 2001,
42, 8215-8217.
(15) For the use of capture-ROMP-release, see: Harned, A. M.;
Hanson, P. R. Org. Lett. 2002, 3, 1007-1010.
(16) Available from Aldrich Chemical Co. as a ∼3:1 mixture of endo:
exo diastereomers. We prepared 1 as a ∼10:1 mixture of endo:exo
diastereomers via AlCl3-catalyzed Diels-Alder reaction of cyclopentadiene
with methyl acrylate (benzene, 50 °C) followed by LiAlH4 reduction.
4
5
6
7
8
PhCH2CH2NH2 TolSO2NCO 2e
n-BuNH2 TolSO2NCO 2f
MeOPhCH2OH PhNCO
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
4f
geraniol
Bn2NH
menthol
PhNCO
PhNCO
PhNCO
98d
9
81d
10
11
12
13
14
15
16
17
18
96d
1-(4H)naphthol PhNCO
84d
BnOH
PhCOCl
PhCOCl
PhCOCl
PhCOCl
PhCOCl
PhCOCl
PhCOCl
94d
C6H11OH
geraniol
phenol
menthol
morpholine
Bn2NH
84d
89d
90d
87d
84d
4g
95d
a Reactions performed with an excess of electrophile as outlined in
Scheme 1. b Polymerization conducted with 1 mol % of Grubbs catalyst
1
11. c Determined by H NMR (no polymer present). d Determined by GC
and confirmed by 1H NMR (no polymer present, see Figure 1 and
supplementary spectra).
1848
Org. Lett., Vol. 4, No. 11, 2002

reactions were complete in 45 min as indicated by GC
analysis. Scavenger 1 was added and the reaction refluxed.
Upon completion (GC analysis), the solvent was removed
in vacuo and degassed CH2Cl2 (0.1 M) was added. Catalyst
11 (1 mol %) was added and the reaction mixture was
refluxed for 30-45 min. Analysis by TLC or GC showed
that no excess scavenger 1 or tagged carbamate 6 was
present. The reaction mixture was then poured into methanol
to precipitate the polymer, which was removed by filtration
using Celite. The resulting carbamates and ureas 3a-e were
isolated in excellent yield and purity.
We also looked at the benzoylation of a variety of amines
and alcohols (entries 12-18, Table 1). Benzoylation using
1 equiv of the nucleophilic species and 2 equiv of benzoyl
chloride in the presence of 8 equiv of Et3N gave the
benzoylated products 4a-g. The excess of benzoyl chloride
was then removed by reaction with 2 equiv of 1, producing
the norbornenyl-tagged compound 7. Once complete, excess
Et3N was removed under reduced pressure. Subsequent
polymerization of 7 and unreacted 1 using 1 mol % of 11,
followed by polymer removal, gave the benzoylated com-
pounds 4a-g in excellent yields and high purity.
In conclusion, we have developed a new scavenge-
ROMP-filter strategy that utilizes the second generation
Grubbs catalyst.17 The method lessens the need for chro-
matographic purification and should be amenable to other
reactions as well as the purification of combinatorial libraries.
Several advantages are apparent: favorable reaction kinet-
ics,20 high-load capacity, and conventional monitoring of
reaction progress. Furthermore, the method is high yielding
and generates products with good to excellent purity.
Figure 1. 1H NMR analysis of purified sulfonyl carbamate 2a and
sulfonyl urea 2f, respectively, using scavenge-ROMP-filter.
precipitation and filtration of the polymers using a suitable
solvent. In this method, the desired products remain in
solution while the unreacted scavenger 1 and tagged reagents
5-7 are co-opted for a rapid in situ ROM polymerization
(20-45 min) as a means of filtering them from the reaction
mixture.
Acknowledgment. This investigation was generously
supported by funds provided by the National Science
Foundation (NSF Career 9984926) and an NIH Dynamic
Aspects in Chemical Biology Training Grant for A.M.H.
Using p-toluenesulfonyl isocyanate as the electrophile, we
looked at the generation of an array of sulfonyl carbamates
and ureas 2a-f utilizing a variety of alcohols and amines
(entries 1-6, Table 1). One equivalent of the nucleophilic
species (amine or alcohol) was added per 2 equiv of the
isocyanate. Once the reaction was complete, excess isocy-
anate was reacted with 2 equiv of 5-norbornene-2-methanol
(1). Subsequent ROM polymerization of all norbornenyl-
tagged molecules (5 and unreacted 1), followed by polymer
removal, gave the desired sulfonyl carbamates and ureas
2a-f in good to excellent yields and high purity as evident
by 1H NMR analysis of crude isolated product (Figute 1).19
Initial attempts at reacting phenyl isocyanate with various
alcohols/amines (entries 7-11, Table 1) focused on perform-
ing the reaction in degassed CH2Cl2, thereby eliminating the
need to change solvents for the polymerization. Unfortu-
nately, while dibenzylamine reacted efficiently in refluxing
CH2Cl2, the reaction with the scavenger alcohol 1 and other
alcohols was slow. To overcome this reactivity problem, we
decided to switch our solvent to toluene which would allow
for higher reaction temperatures.
Supporting Information Available: Detailed experi-
1
mental procedures and H NMR spectra of crude products
obtained by our method. This material is available free of
charge via the Internet at http://acs.pubs.org.
OL0257880
(17) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(18) The importance of utilizing the second generation Grubbs catalyst
is demonstrated in a comparative study, see ref 15.
(19) 1H NMR spectra of all crude products are available in the Supporting
Information.
(20) A comparative experiment of the reaction kinetics was made between
the norbornene-based scavenger 1 and its comparable solid-phase equivalent,
the hydroxymethyl resin (purchased from Irori). In this study, each alcohol
scavenger (1.2 equiv) was tested for its reactivity toward the three
electrophiles (1 equiv): p-toluenesulfonyl isocyanate, phenyl isocyanate,
and benzoyl chloride. In the cases of p-TsNCO and the PhCOCl (0 °C to
rt), the norbornene-based scavenger reacted instantaneously with the
electrophile, depleting its concentration to zero before any analysis could
take place; in the PhNCO case, the tagged-scavenger reacted completely
with the electrophile in 50 min (toluene, 100 °C). The resin-bound scavenger
reacted only slightly slower for the p-TsNCO (15 min); however, for
PhCOCl and PhNCO, the resin-bound scavenger was dramatically slower
(>2 h for PhCOCl and >12 h for PhNCO).
To this end, various alcohols and dibenzylamine were
treated with phenyl isocyanate in refluxing toluene to produce
carbamates and ureas 3a-e (entries 7-11, Table 1). The
Org. Lett., Vol. 4, No. 11, 2002
1849