High-load, hybrid Si-ROMP reagents

Article abstract of DOI:10.1021/ol102239h

The combination of norbornenyl-tagged (Nb-tagged) silica particles and functionalized Nb-tagged monomers for the generation of hybrid Si-ROMP reagents and scavengers is reported. Specifically Si-ROMP-derived bis-acid chloride, dichlorotriazine, and triphenylphosphine scavenger/reagents have been grafted from the surface of silica particles utilizing surface-initiated, ring-opening metathesis polymerization (ROMP). These hybrid polymeric materials combine the physical properties of current immobilized silica reagents and represent a key advancement in load by merging the inherent tunable properties of the ROMP-derived oligomers with silica supports for application in a parallel synthesis.

Full text of DOI:10.1021/ol102239h

ORGANIC
LETTERS
2011
Vol. 13, No. 1
4-7
High-Load, Hybrid Si-ROMP Reagents
Alan Rolfe, Joanna K. Loh, Pradip K. Maity, and Paul R. Hanson*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe, Lawrence,
Kansas 66045, United States, and The UniVersity of Kansas Center for Chemical
Methodologies and Library DeVelopment (KU-CMLD), 2034 Becker DriVe, Delbert M.
Shankel Structural Biology Center, Lawrence, Kansas 66047, United States
phanson@ku.edu
Received September 18, 2010
ABSTRACT
The combination of norbornenyl-tagged (Nb-tagged) silica particles and functionalized Nb-tagged monomers for the generation of hybrid
Si-ROMP reagents and scavengers is reported. Specifically Si-ROMP-derived bis-acid chloride, dichlorotriazine, and triphenylphosphine scavenger/
reagents have been grafted from the surface of silica particles utilizing surface-initiated, ring-opening metathesis polymerization (ROMP).
These hybrid polymeric materials combine the physical properties of current immobilized silica reagents and represent a key advancement in
load by merging the inherent tunable properties of the ROMP-derived oligomers with silica supports for application in a parallel synthesis.
The development of new immobilized reagents and scaven-
gers for application in facilitated synthetic protocols is an
important facet of drug discovery. The ability to rapidly
generate collections of small molecules without the need for
time-consuming, expensive purification protocols has inspired
the development of immobilized reagents and scavengers.
Since the introduction of polystyrene immobilized resins,1
a variety of advancements have been developed for the
immobilization of functionalized reagents including silica,2
fluorous,3 monolith,4 and soluble polymers generated from
ring-opening metathesis polymerization (ROMP).5
nologies.6 Despite the large investment in the design and
advancement of several platforms, limited advancements in
the immobilized reagent cartridges for in-line diversification
or purification have been made. Though current functional-
ized silica reagents have circumvented many of the traditional
limitations associated with classical resin-bound reagents,
current available reagents suffer from low load levels
typically expressed in mmol/g.
Recently, surface functionalization of nanoparticles7 has
emerged as a well-established method for the preparation of
polymeric hybrid materials as reported by Buchmeiser and
A pivotal emerging technology in drug discovery has been
the development and utilization of automated parallel tech-
(5) For reviews concerning ROMP reagents, see: (a) Barrett, A. G. M.;
Hopkins, B. T. Ko¨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 DeV. 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 Metathesis; Grubbs,
R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003; pp 361-402. (d)
Harned, A. M.; Zhang, M.; Vedantham, P.; Mukherjee, S.; Herpel, R. H.;
Flynn, D. L.; Hanson, P. R. Aldrichimica Acta 2005, 38, 3–16.
(1) (a) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149–2154. (b)
Takashima, H.; Vigneaud, V. D.; Merrifield, R. B. J. Am. Chem. Soc. 1968,
90, 1323–1325. (c) Baxendale, I. R.; Brusotti, G.; Matsuoka, M.; Ley, S. V.
J. Chem. Soc., Perkin Trans. 1 2002, 143–154. (d) Storer, R. I.; Takemoto,
T.; Jackson, P. S.; Brown, D. S.; Baxendale, I. R.; Ley, S. V. Chem.sEur.
J. 2004, 10, 2529–2547. (e) Baxendale, I. R.; Ley, S. V.; Piutti, C. Angew.
Chem., Int. Ed. 2002, 41, 2194–2197.
(2) Lu, J.; Toy, P. H. Chem. ReV. 2009, 109, 815–838.
(6) (a) Gerhard, J.; Kirschning, A. Chem.sEur. J. 2003, 9, 5708–5723.
(b) Hornung, C. H.; Hallmark, B.; Mackley, M. R.; Baxendale, I. R.; Ley,
S. V. AdV. Synth. Catal. 2010, 352, 1736–1745. (c) Hornung, C. H.;
Hallmark, B.; Baumann, M.; Baxendale, I. R.; Ley, S. V.; Hester, P.;
Clayton, P.; Mackley, M. R. Ind. Eng. Chem. Res. 2010, 49, 4576–4582.
(d) Comer, E.; Organ, M. G. J. Am. Chem. Soc. 2005, 127, 8160–8167.
(3) (a) Curran, D. P. Aldrichimica Acta 2006, 39, 3–9. (b) Curran, D. P.
Med. Res. ReV. 2000, 72, 1649–1653.
(4) (a) Bandari, R.; Knolle, W.; Prager-Duschke, A.; Buchmeiser, M. R.
Macromolecules 2007, 28, 2090–2094. (b) Mayr, M.; Mayr, B.; Buchmeiser,
M. R. Angew. Chem., Int. Ed. 2001, 40, 3839–3842.
10.1021/ol102239h  2011 American Chemical Society
Published on Web 12/01/2010

co-workers.8 Such hybrid nanomaterials combine the physical
properties of the inorganic shell (particle size, pore, and
shape) with the tunable properties of the grafted organic
polymer.9 Key reports have demonstrated the potential scope
of surface-initiated ROM polymerization for the grafting of
organic polymers from inorganic nanoparticles,10 carbon
nanotubes,11 metal surfaces,12 and resins.13
Recently, ROMP-derived oligomeric and polymeric re-
agents/scavengers have surfaced for application in facilitated
synthetic protocols. These reagents possess several inherent
characteristics that address classical limitations associated
with traditional immobilized reagents, that is, load, tunable
properties, heterogeneous reaction kinetics, and so on.5,14-16
Inspired by these developments, it was envisioned that, by
combining the inherent high-load, tunable properties of
soluble ROMP-derived oligomers with an insoluble silica
support, a new variety of hybrid immobilized functionalized
reagents could be achieved. Unlike current methods of
functionalizing the surface of silica particles, the application
of surface-initiated ROM polymerization addresses the
limitation of load by allowing the grafting of multiple
monomer units into an oligomeric chain from each Nb-tagged
site on the silica particle (Figure 1).
Figure 1. (a) Standard functionalization of silica reagents. (b)
Functionalization of Nb-tagged silica particles utilizing surface-
initiated ROM polymerization.
ated the desired high-load soluble scavenger possessing a
theoretical load of 9.1 mmol/g. Therefore, it was envisioned
that preactivation of Nb-tagged silica 2 with Grubbs catalyst
would generate a catalyst-armed surface (CAS) capable of
efficient polymerization off the silica surface with Nb-tagged
monomer 3 while maintaining the high-load nature of the
reagent.
Utilizing a protocol reported by Buchmeiser and co-
workers in 2000,8 activated spherical silica 1 (70 Å, 20 µm
particle size) was tagged with 5-(bicycloheptenyl)-triethoxy
silane, followed by capping with trimethoxymethylsilane and
dimethoxydimethylsilane to yield the desired Nb-tagged silica
(Si-Nb) 2 (Scheme 1). With this tagged nanoparticle in
We initially focused on the synthesis of a Si-ROMP-
derived bis-acid chloride scavenger (Si-OBAC) by starting
with the corresponding Nb-tagged BAC-functionalized mono-
mer utilized for the generation of OBAC soluble oligomers.17
Previously, simple ROM polymerization of the corresponding
Nb-tagged bis-acid chloride monomer 3 using metathesis
catalyst [(IMesH2)(PCy3)(Cl)2RudCHPh; cat-B],18,19 gener-
Scheme 1
.
Synthesis of Silica-Grafted Oligomeric Bis-Acid
(7) (a) Graf, C.; Vossen, D. I. J.; Imhof, A.; van Blaaderen, A. Langmuir
2003, 19, 6693–6700. (b) Schneider, G.; Decher, G. Nano Lett. 2004, 4,
1833–1839.
Chloride 4 and 5 (Si-OBAC)
(8) (a) Buchmeiser, M. R.; Atzl, N.; Bonn, G. K. J. Am. Chem. Soc.
1997, 119, 9166–9174. (b) Ambrose, D.; Fritz, J. S.; Buchmeiser, M. R.;
Altz, N.; Bonn, G. K. J. Chromatogr., A 1997, 786, 259–268. (c)
Buchmeiser, M. R.; Sinner, F.; Mupa, M.; Wurst, K. Macromolecules 2000,
33, 32–39. (d) Eder, K.; Reichel, E.; Schottenberger, H.; Huber, C. G.;
Buchmeiser, M. R. Macromolecules 2001, 34, 4334–4341.
(9) Kim, N. Y.; Jeon, N. L.; Choi, I. S.; Takami, S.; Harada, Y.; Finnie,
K. R.; Girolami, G. S.; Nuzzo, R. G.; Whitesides, G. M.; Laibinis, P. E.
Macromolecules 2000, 33, 2793–2795.
(10) (a) Kong, B.; Lee, J. K.; Choi, I. S. Langmuir 2007, 23, 6761–
6765. (b) Faulkner, C. J.; Fischer, R. E.; Jennings, G. K. Macromolecules
2010, 43, 1203–1209.
(11) Jeong, W.; Kessler, M. R. Chem. Mater. 2008, 20, 7060–7068.
(12) Rutenberg, I. M.; Scherman, O. A.; Grubbs, R. H.; Jiang, W.;
Garfunkel, E.; Bao, Z. J. Am. Chem. Soc. 2004, 126, 4062–4063.
(13) Lapinte, V.; Montembault, V.; Houdayer, A.; Fontaine, L. J. Mol.
Catal. A: Chem. 2007, 276, 219–225.
(14) (a) Long, T.; Maity, P. K.; Samarakoon, T. B.; Hanson, P. R. Org.
Lett. 2010, 12, 2904–2907. (b) Rolfe, A.; Probst, D.; Volp, K.; Omar, I.;
Flynn, D.; Hanson, P. R. J. Org. Chem. 2008, 73, 8785–8790. (c) Stoianova,
D. S.; Yao, L.; Rolfe, A.; Samarakoon, T.; Hanson, P. R. Tetrahedron Lett.
2008, 49, 4553–4555. (d) Herpel, R. H.; Vedantham, P.; Flynn, D. L.;
Hanson, P. R. Tetrahedron Lett. 2006, 47, 6429–6432. (e) Harned, A. M.;
He Song, H.; Toy, P. H.; Flynn, D. L.; Hanson, P. R. J. Am. Chem. Soc.
2005, 127, 52–53. (f) Barrett, A. G. M.; Hopkins, B. T.; Love, A. C.;
Tedeschi, L. Org. Lett. 2004, 6, 835–837. (g) Arstad, E.; Barrett, A. G. M.;
hand, the surface was armed with metathesis catalyst cat-B
(0.6-0.8 equiv), followed by addition of the Nb-tagged BAC
monomer 3 to rapidly generate the desired hybrid material,
Si-OBAC50 4.20,21 A number of key parameters were critical,
including reaction concentration and prearming of the silica
surface with 0.8 equiv of cat-B before the addition of the
Nb-tagged monomeric species. This was important to ensure
Tedeschi, L. Tetrahedron Lett. 2003, 44, 2703–2707
(15) (a) Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S. Org. Lett. 1999,
1, 1083–1086. (b) Roberts, R. S. J. Comb. Chem. 2005, 7, 21–32
.
.
(16) (a) Zhang, M.; Flynn, D. L.; Hanson, P. R. J. Org. Chem. 2007,
72, 3194–3198. (b) Harned, A. M.; Sherrill, W. M.; Flynn, D. L.; Hanson,
P. R. Tetrahedron 2005, 61, 12093–12099. (c) Zhang, M.; Moore, J. D.;
Flynn, D. L.; Hanson, P. R. Org. Lett. 2004, 6, 2657–2660
.
(17) Moore, J. D.; Byrne, R. J.; Vedantham, P.; Flynn, D. L.; Hanson,
P. R. Org. Lett. 2003, 5, 4241–4244.
Org. Lett., Vol. 13, No. 1, 2011
5

that all the metathesis catalyst was attached from the Nb-
tagged silica surface and potentially preventing polymeri-
zation of the Nb-tagged monomer 3 by any free catalyst in
solution.20
After optimization of the reaction conditions, Si-OBAC50
4 possessing a theoretical load of 2.74 mmol/g, was readily
accessed as a free-flowing solid on the gram scale.22,23
Utilizing the inherent tunable characteristics of ROMP-
derived oligomers, the theoretical load of this hybrid material
was further increased by extending the oligomeric chain
length to 100 monomeric units (100-mer), yielding Si-
OBAC100 5 possessing a theoretical load of 5.26 mmol/g
(Scheme 1). This key advancement exploits the inherent
properties of Si-ROMP hybrid materials, whereby simply
increasing the ratio of monomer 3 to silica 2 (i.e., 50:1 to
100:1) increases the polymer chain length and hence gives
rise to increased theoretical loads. Furthermore, Si-ROMP
scavengers 4 and 5 are highly favorable in comparison to
commercially available Si-immobilized scavengers of nu-
cleophiles with loads ranging from 0.7-1.2 mmol/g.24 Taken
collectively, this represents a significant cost savings and
environmental impact to the field.
Figure 2
Si-OBAC100 100-mer 5 (right).
. SEM images of Si-OBAC50 4 50-mer (left) and
Scheme 2
.
Benzoylation Reactions Utilizing Si-OBAC50 4 To
Scavenge Excess Alcohol
When scanning electron microscopy (SEM) was used,
detailed images of the hybrid materials surface morphology
were obtained. Notably, the comparison between Si-OBAC50
4 and the longer chained Si-OBAC100 5 is visually noticed
by the SEM images (Figure 2).
With Si-OBAC50 4 in hand, the hybrid material was
evaluated for the scavenging of nucleophilic species. A
variety of alcohols were benzoylated to yield the correspond-
ing esters 6a-h, whereby excess alcohol (0.5 equiv) was
scavenged efficiently with Si-OBAC50 4 (Scheme 2).25 When
1.0 equiv of Si-OBAC50 4 was used, the desired esters 6a-h
were isolated in high crude purity and conversion after simple
filtration thru a Celite SPE, demonstrating the efficient ability
of 4 to work as a facile scavenger without the need for
conventional silica chromatography. Identical results were
observed when utilizing the high-load, hybrid Si-OBAC100
5, demonstrating comparable scavenging efficiency to the
previously reported oligomeric OBAC derivative.17
Building on these results, the project was expanded to the
synthesis of additional Si-ROMP hybrid reagents and
scavengers. In this regard, investigations focused on the
synthesis of the corresponding Si-hybrid materials
Si-ODCT50 7 and Si-OTPP50 9, synthesized via the grafting
of the corresponding Nb-tagged dichlorotriazine,14b and Nb-
tagged triphenylphosphine (Figure 3).14e When the same
(18) Scholl, M.; Ding, Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953–956
.
(19) A variety of metathesis catalysts were investigated, including
[(PCy3)2(Cl)2RudCHPh; cat-A], [(IMesH2)(PCy3)(Cl)2RudCHPh; cat-B],
and the Hoveyda-Grubbs second-generation catalyst. In all cases studied,
cat-B was ideal in both thermal stability and initiation rate.
(20) Si-OBAC50 denotes the inorganic surface [Si], followed by the
ROMP-derived oligomer grafted [OBAC], followed by the theoretical
number of Nb monomer units grafted.
(21) We have previously found that there is a good correlation between
the mol % of Grubbs catalyst added and the Gaussian distribution of
oligomers formed, which is the case with several other oligomers formed
[see ref 5d]. We have made these reagents several times with good
reproducibility and consistency. MALDITOF and GPC data are normally
attained on all oligomers; however, both methods have failed to give good
results for previously published reactive oligomers.
(22) Control reaction was run with activated silica, 50 equiv of OBAC
monomer in CH2Cl2 (0.8 M), for 30 min. After such time, the resulting
crude mixture did not gel as observed for Si-OBAC hybrid materials and
was instead isolated via precipitation in Et2O.
Figure 3. Synthesis of silica-grafted oligomeric dichlorotriazine 7
and 8 (Si-ODCT50) and triphenylphosphine 9 and 10 (Si-OTTP50).
(23) OBAC load stated as mmol/g of acid chloride (ROCl) and further
details are reported in ref 17. For load calculation, see Supporting
Information S4.
(24) www.biotage.com, www.silicycle.com, and www.fluorous.com
(accessed June 2010).
(25) In comparison to their soluble variants (OBAC, ref 17 and ODCT
ref 14b) under identical conditions, no difference in reaction stoichiometry
and kinetics was observed. Currently there is no commercially available
silica immobilized bis-acid chloride variant for direct comparison, however,
Si-ROMP reagents reported within this manuscript produced similar
conversions/yields under identical conditions to their soluble variants (OBAC
and ODCT).
protocol reported for the synthesis of Si-OBAC50 4 (Scheme
1) was used, Si-ODCT50 7 (theoretical load ) 2.79 mmol/
g) and Si-OTPP50 9 (theoretical load ) 1.4 mmol/g) were
successfully isolated as free-flowing powders. The theoretical
load of both reagents was further increased by extending the
oligomeric length to 100 monomer units, yielding the
corresponding materials Si-ODCT100 8 (3.7 mmol/g)26 and
Si-OTPP100 10 (2.3 mmol/g), respectively.24 Both reagents
6
Org. Lett., Vol. 13, No. 1, 2011

are highly favorable in comparison to commercially available
immobilized silica reagents.24 When SEM was used, detailed
images of 7 and9 were obtained, demonstrating once again
the morphology of the hybrid materials obtained via surface-
initiated ROMP off the spherical silica particles (Figure 4).
Scheme 3. Amide Coupling Reactions Utilizing Si-ODCT
surface (CAS)-initiated polymerization was key to function-
alization of units off the silica particle surface. When this
technology was used, a high load Si-ROMP derived bis-acid
chloride (Si-OBAC) scavenger was successfully synthesized
and utilized in batch. Additionally, high-load, Si-ROMP-
derived dichlorotriazine (Si-ODCT) and triphenylphosphine
(Si-OTP) were readily prepared. SEM imaging was utilized
to demonstrate the successful grafting of the corresponding
oligomer and the inherent morphology of the hybrid materi-
als. Current efforts are focusing on the application and
utilization of high load Si-ROMP reagents in parallel
synthesis and continuous flow-through protocols for in-line
purification and diversification of small molecules.
Figure 4. SEM images of Si-ODCT50 50-mer 7 (left) and (b) Si-
OTPP50 50-mer 9 (right).
We have previously reported the versatile utilization of
oligomeric dichlorotriazine (ODCT) as an efficient coupling
reagent, scavenger, and activator in parallel synthesis.14b In
this regard, Si-ODCT50 was investigated as a coupling
reagent for the synthesis of amides 11a-h from simple acids
and amines under mild conditions (Scheme 3).
The desired amides 11 a-h were efficiently coupled
together utilizing Si-ODCT50 7 in high conversion and crude
purity without the need for standard chromatography. It is
key to note that Si-ODCT50 7 demonstrated the same
efficiency in comparison to the soluble oligomeric version
ODCT for the formation of amides.26
Acknowledgment. This research was made possible by
the National Institute of General Medical Sciences [NIH-
STTR R41 GM076765, NIH P050-GM069663]. We ac-
knowledge Dr. David S. Moore and Ms. Heather Shinogle
for carrying out SEM analysis (KU). We thank Materia Inc.
for providing metathesis catalyst.
In conclusion, the combination of Nb-tagged silica par-
ticles and functionalized Nb-tagged monomers efficiently
yields high-load, hybrid Si-ROMP reagents. A catalyst-armed
Supporting Information Available: Experimental details
and spectral characterization for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(26) For comparison to reported uses of silica-immobilized dichlorot-
riazine, see: Kowalski, J. A.; Leonard, S. F.; Lee, G. E., Jr. J. Comb. Chem
2006, 8, 774–779.
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