ROMP-derived oligomeric phosphates for application in facile benzylation

Article abstract of DOI:10.1021/ol1006604

The development of new ROMP-based oligomeric benzyl phosphates (OBP _n) is reported for use as soluble, stable benzylating reagents. These oligomeric reagents are readily synthesized from commercially available materials and conveniently polymerized and purified in a one-pot process, affording bench-stable, pure white, free-flowing solids on multigram scale. Utilization in benzylation reactions with a variety of nucleophiles is reported.

Full text of DOI:10.1021/ol1006604

ORGANIC
LETTERS
2010
Vol. 12, No. 13
2904-2907
ROMP-Derived Oligomeric Phosphates
for Application in Facile Benzylation
Toby R. Long,†,‡ Pradip K. Maity,† Thiwanka B. Samarakoon,† and
Paul R. Hanson*,†,‡
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045-7582, and The Center for Chemical Methodologies and
Library DeVelopment at the UniVersity of Kansas (KU-CMLD), 2034 Becker DriVe,
Del Shankel Structural Biology Center, Lawrence, Kansas 66047
phanson@ku.edu
Received March 19, 2010
ABSTRACT
The development of new ROMP-based oligomeric benzyl phosphates (OBPn) is reported for use as soluble, stable benzylating reagents. These
oligomeric reagents are readily synthesized from commercially available materials and conveniently polymerized and purified in a one-pot
process, affording bench-stable, pure white, free-flowing solids on multigram scale. Utilization in benzylation reactions with a variety of
nucleophiles is reported.
The development of new immmobilized reagents for the
production of libraries for high-throughput screening is an
important element in drug discovery. In this regard, new and
improved immobilized reagents with tunable properties have
emerged as critical components in facilitated synthetic
protocols, particularly within the arena of combinatorial and
green technologies.1,2 Consequently, this has driven the
development of an array of polymer-bound supports, re-
agents, and scavengers for streamlining synthetic methods
into simple mix, filter, and evaporate protocols.1,2 Despite
many salient attributes of current immobilized platforms,
limitations in load capacity, reaction kinetics, means of
delivery, and stability continue to warrant efforts in this
area.3 Among these, ring-opening metathesis (ROM)
polymerization of functionalized norbornenes has surfaced
as a powerful tool in the generation of high-load,
immobilized reagents with tunable properties.4-6 In this
regard, we report the development of new ROMP-based
† University of Kansas.
‡ KU-CMLD.
(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. 2001, 40, 650–679. (d) Eames,
J.; Watkinson, M. Eur. J. Org. Chem. 2001, 1213–1224. (e) Strohmeier,
G. A.; Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 621–624. (f) Lesch,
B.; Thomson, D. W.; Lindell, S. D. Comb. Chem. High Throughput
(3) (a) Studer, A.; Curran, D. P. Tetrahedron 1997, 53, 6681–6696. (b)
Hjerten, S.; Li, Y.-M.; Liao, J. L.; Mankazato, K.; Mohammad, J.;
Pettersson, G. Nature 1992, 356, 810–811. (c) Baumann, M.; Baxendale,
I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D. Org. Biomol. Chem. 2008, 6,
1577–1586.
Screening 2008, 11, 31–36
.
(2) For reviews concerning soluble polymers, see: (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) Dickerson, T. J.; Reed, N. N.; Janda,
K. D. Chem. ReV. 2002, 102, 3325–3344. (d) Haag, R. Chem.sEur. J. 2001,
7, 327–335. (e) Haag, R.; Sunder, A.; Hebel, A.; Roller, S. J. Comb. Chem.
2002, 4, 112–119. (f) Bergbreiter, D. E. Chem. ReV. 2002, 102, 3345–3384.
(4) (a) Barrett, A. G. M.; Hopkins, B. T.; Kobberling, J. Chem. ReV.
2002, 102, 3301–3324. (b) Harned, A. M.; Probst, D. A.; Hanson, P. R.
Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003;
Vol. 2, pp 361-402. (c) Flynn, D. L.; Hanson, P. R.; Berk, S. C.; Makara,
G. M. Curr. Opin. Drug DiscoVery DeV. 2002, 5, 571–579. (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.
(g) Bergbreiter, D. E.; Tian, J.; Hongfa, C. Chem. ReV. 2009, 109, 530–582
.
10.1021/ol1006604  2010 American Chemical Society
Published on Web 06/03/2010

oligomeric benzyl phosphates (OBPn) for use as soluble,
stable benzylating reagents.
Interest in further improvements17 of such protocols has led
to the study reported herein.
The innate properties of phosphates as leaving groups have
inspired the current study aimed at developing oligomeric
phosphate-based reagents. While phosphates have been
uniquely tailored to play vital roles in nature,7 only recently
have they found widespread use in synthetic methodology
and total synthesis.8 This resurgence is primarily attributed
to their stability, facile assembly, and ideal monoanionic pKa
profiles.9 Despite these attributes, synthetic oligomeric-based
phosphates and other phosphorus-containing materials have
found applications primarily in the production of flame-
retardant materials10 with limited use in novel therapeutic
applications.11 To the best of our knowledge, the literature
is void of immobilized phosphate-based alkylating/benzy-
lating agents.
The synthesis of oligomeric benzyl phosphate 6 was
envisioned to occur via reduction of endo norbornenyl
anhydride 1 to the corresponding diol, followed by phos-
phorylation and subsequent condensation with benzyl alco-
hol. However, repeated attempts to polymerize the endo
isomer of monomer 5 with a variety of metathesis catalysts
resulted in incomplete conversions. Plausibly, both steric and
electronic interactions of the PdO bond of the resulting endo
isomer could interfere with catalyst/olefin activation or the
subsequent propagation step.
Attention was next directed toward synthesis of the
thermodynamic exo isomer (Scheme 1). Several thermal
The benzylation of amines and alcohols continues to
serve as one of the most utilized protecting group
strategies in organic synthesis due to its ease of incorpora-
tion and removal.12,13,7b In addition, benzylation has
emerged as a key diversification reaction in medicinal/
combinatorial chemistry approaches as well as diversity-
oriented synthesis.14 This continued use has spurred devel-
Scheme 1
.
Synthesis of the Oligomeric Benzyl Phosphate
(OBP)
opment of
a number of alternative approaches to
benzylation.15,16 Among these, two ROMP-derived benzy-
lating agents were recently developed in our laboratory.5c,16b
(5) (a) Rolfe, A.; Probst, D.; Volp, K.; Omar, I.; Flynn, D.; Hanson,
P. R. J. Org. Chem. 2008, 73, 8785–8790. (b) Stoianova, D. S.; Yao, L.;
Rolfe, A.; Samarakoon, T.; Hanson, P. R. Tetrahedron Lett. 2008, 49, 4553–
4555. (c) Zhang, M.; Flynn, D. L.; Hanson, P. R. J. Org. Chem. 2007, 72,
3194–3198. (d) Roberts, R. S. J. Comb. Chem. 2005, 7, 21–32. (e) Harned,
A. M.; Sherrill, W. M.; Flynn, D. L.; Hanson, P. R. Tetrahedron 2005, 61,
12093–12099. (f) Arstad, E.; Barrett, A. G. M.; Tedeschi, L. Tetrahedron
Lett. 2003, 44, 2703–2707. (g) Barrett, A. G. M.; Hopkins, B. T.; Love,
A. C.; Tedeschi, L. Org. Lett. 2004, 6, 835–837.
(6) Vedantham, P.; Zhang, M.; Gor, P. J.; Huang, M.; Georg, G. I.;
Lushington, G. H.; Mitscher, L. A.; Ye, Q.-Z.; Hanson, P. R. J. Comb.
Chem. 2008, 10, 195–203.
isomerization reactions of the inexpensive endo carbic
anhydride 1 were performed on large scale using classical
methods.18 Sequential recrystallizations in toluene yielded
exo product 2 with diastereomeric ratios progressively
increasing and yields decreasing with each recrystallization,
[i.e., dr )15:1 and 39% yield after three recrystallizatons,
dr )29:1 and 34% yield after four, up to dr )84:1 and 20%
(7) (a) Westheimer, F. H. Science 1987, 235, 1173–1178. (b) Paquette,
L. A. In Encyclopedia of Reagents for Organic Synthesis, 1st ed.; John
Wiley and Sons: New York, 1995; pp 316-318.
(8) (a) Yanagisawa, A.; Nomura, N.; Noritake, Y.; Yamamoto, H.
Synthesis 1991, 12, 1130–1136. (b) Torneiro, M.; Fall, Y.; Castedo, L.;
Mourino, A. J. Org. Chem. 1997, 62, 6344–6352. (c) Murphy, K. E.;
Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4690–4691. (d) Williams,
D. R.; Heidebrecht, R. W., Jr. J. Am. Chem. Soc. 2003, 125, 1843–1850.
(e) Fuwa, H.; Sasaki, M. Heterocycles 2008, 76, 521–539. (f) Thomas, C. D.;
McParland, J. P.; Hanson, P. R. Eur. J. Org. Chem. 2009, 5487–5500. (g)
Smith, A. G.; Johnson, J. S. Org. Lett. 2010, 12, 1784–1787.
(9) (a) Nicolaou, K. C.; Shi, G. Q.; Gunzner, J. L.; Gaertner, P.; Yang,
Z. J. Am. Chem. Soc. 1997, 119, 5467–5468. (b) La Cruz, T. E.;
Rychnovsky, S. D. J. Org. Chem. 2007, 72, 2602–2611. (c) Lapointe, D.;
Fagnou, K. Org. Lett. 2009, 11, 4160–4163.
(15) (a) Loris, A.; Perosa, A.; Selvia, M.; Tundo, P. J. Org. Chem. 2004,
69, 3953–3956. (b) Shieh, W.-C.; Lozanov, M.; Loo, M.; Repic, O.;
Blacklock, T. J. Tetrahedron Lett. 2003, 44, 4563–4565. (c) Shieh, W.-C.;
Lozanov, M.; Repic, O. Tetrahedron Lett. 2003, 44, 6943–6945. (d) Huang,
W.; He, B. Chin. J. React. Polym. (Engl.) 1992, 1, 61–70. (e) Hunt, J. A.;
Roush, W. R. J. Am. Chem. Soc. 1996, 118, 9998–9999. (f) Rueter, J. K.;
Nortey, S. O.; Baxter, E. W.; Leo, G. C.; Reitz, A. B. Tetrahedron Lett.
1998, 39, 975–978. (g) Baxter, E. W.; Rueter, J. K.; Nortey, S. O.; Reitz,
A. B. Tetrahedron Lett. 1998, 39, 979–982. (h) Takahashi, T.; Ebata, S.;
Doi, T. Tetrahedron Lett. 1998, 39, 1369–1372.
(10) (a) Morgan, A. B.; Tour, J. M. J. Appl. Polym. Sci. 1999, 73, 707–
718. (b) Wang, J.; Mao, H.-Q.; Leong, K. W. J. Am. Chem. Soc. 2001,
123, 9480–9481. (c) Iliescu, S.; Manoviciu, I.; Ilia, G.; Dehelean, G. Roum.
Chem. Q. ReV. 1997, 5, 267–277. (d) Kobayashi, S.; Tokunoh, M.; Saegusa,
T. Macro. Mol. 1986, 19, 466–469. (e) Allcock, H. R.; de Denus, C. R.;
Prange, R.; Laredo, W. R. Macromolecules 2001, 34, 2757–2765. (f)
Seeberger, P. H. Chem. Soc. ReV. 2008, 37, 19–28.
(16) For recent benzylation via activation of benzyl alcohols see: (a)
Poon, K. W. C.; House, S. E.; Dudley, G. B. Synlett 2005, 3142–3144. (b)
Zhang, M.; Moore, J. D.; Flynn, D. L.; Hanson, P. R. Org. Lett. 2004, 6,
2657–2660. (c) Jha, M.; Enaohwo, O.; Marcellus, A. Tetrahedron Lett. 2009,
50, 7184–7187. (d) Martinez, R.; Ramon, D. J.; Yus, M. Org. Biomol. Chem.
2009, 7, 2176–2181. (e) Zhang, C.; Gao, X.; Zhang, J.; Peng, X. Synlett
2010, 261–265.
(11) Kane, R. R.; Lee, C. S.; Drechsel, K.; Hawthorne, M. F. J. Org.
Chem. 1993, 58, 3227–3228.
(12) March, J. AdVanced Organic Chemistry, 4th ed.; Wiley: New York,
1991
.
(13) Greene, T. W.; Wuts, P. G. M. In ProtectiVe Groups in Organic
Synthesis, 4th ed.; John Wiley and Sons: New York, 2007; pp 102-148.
(14) (a) Dolle, R. E.; Le Bourdonnec, B.; Goodman, A. J.; Morales,
G. A.; Thomas, C. J.; Zhang, W. J. Comb. Chem. 2009, 11, 739–790. (b)
Fenster, E.; Rayabarapu, D. K.; Zhang, M.; Mukherjee, S.; Hill, D.;
Neuenswander, B.; Schoenen, F.; Hanson, P. R.; Aube´, J. J. Comb. Chem.
2008, 10, 230–234.
(17) (a) The synthesis of oligomeric benzylsulfonium salts requires 5
steps and the use of benzyl bromides. These reagents were not soluble in
typical organic solvents.5c (b) The oligomeric sulfonate esters were used in
a “catch and release” protocol whereby benzyl alcohols were reacted after
polymerization.16b
(18) Craig, D. J. Am. Chem. Soc. 1951, 73, 4889–4892.
Org. Lett., Vol. 12, No. 13, 2010
2905

yield after six]. Reduction of 2 with LiAlH4 yielded diol 3
as a clear, viscous oil with good yield. Phosphorylation of
the exo diol 3 was performed using distilled POCl3 and Et3N
in the presence of catalytic DMAP to yield phosphorochlo-
ridate 4 as a white solid in moderate yields. This was
conveniently stored as a solid over argon in a desiccator for
use in preparing the various reagents for up to three months.
Addition of 4 into a solution containing benzyl alcohol,
NMI, and CH2Cl2 at room temperature cleanly afforded the
benzyl phosphate 5 in good yields and purity. Polymerization
of 5 and other phosphate analogues of this type in the
presence of (IMesH2)(PCy3)(Cl)2RudCHPh (cat. B)19 oc-
curred rapidly at room temperature resulting in formation
of insoluble and unusable gels. However, polymerization with
RuCl2(PCy3)2dCHPh (cat. A)20 cleanly afforded the oligo-
meric reagent with desirable characteristics.21 Following
polymerization, the reaction was quenched with ethyl vinyl
ether (EVE) and stirred for 30 min. A basic workup involving
the Pederson protocol22 was applied in the same pot until
cat. A was visibly removed as indicated by precipitate
formation and lack of coloration. The resulting solution was
washed several times with water, dried over MgSO4, and
concentrated to critical viscosity.23 Precipitation via dropwise
addition into anhydrous Et2O afforded oligomeric benzyl
phosphate (OBPn) 6 as a free-flowing white solid where n
) relative lengths of 20-, 50-, and 100-mers, each displaying
slightly different solubility profiles.24
Table 1. Benzylation of N-, O-, and S-Nucleophiles Using
OBP20
a Isolated yields after filtration through a silica SPE. b Purities calculated
using GC and further confirmed by 1H NMR. c Percent conversion and ratio
of mono- to dibenzylated amine as found by GC-MS. d Percent conversion
and ratio of mono- to dibenzylated amine as found by GC-MS. e Reaction
was performed with OBP50.
Et2O, filtered via silica SPE, and concentrated under vacuum
to afford the corresponding benzylated analogue(s) in good
to excellent yields and high purity. The resulting monoan-
ionic oligomeric phosphate was found to be water-soluble
at elevated temperatures and remained soluble on cooling
to room temperature. This observation would be of particular
importance in potential large-scale applications for the
removal of spent oligomer without the need for precipitation.
The oligomeric benzyl phosphate 20-mer (OBP20) was then
investigated for benzylation of various amines (Scheme 2,
Scheme 2. Benzylation of Morpholine
Table 2. Synthesis of Various OBP Analogues
Table 1). The reagent was delivered either as a free-flowing
powder or as a stock solution in anhydrous CHCl3 alongside
a catalytic amount of tetrabutylammonium iodide.25 During
the reaction, precipitation of the resulting oligomeric phos-
phate monoanion typically occurred within a 0.5-2 h period
after addition of the nucleophile. The mother liquor was
subsequently concentrated over silica or precipitated into
(19) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956.
(20) (a) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
1996, 118, 100–110. (b) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs,
R. H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2039–2041.
(21) These characteristics include homogeneity and the ability to achieve
the necessary critical viscocity for precipitation.
(22) Pederson, R. L.; Fellows, I. M.; Ung, T. A.; Ishihara, H.; Hajela,
S. P. AdV. Synth. Catal. 2002, 344, 728–735.
(23) Critical viscosity described in these terms is the optimum viscosity
to achieve a free-flowing precipitate.
(24) See Supporting Information for solubility tables of OBPn. For
information regarding Gaussian distribution of oligomers see ref 5a.
(25) We have recently formulated ROMP-tabs, whereby premeasured
OBP20 tablets can be conveniently added to the reaction.
a Yields correspond to monomeric phosphates. Quantitative conversions
were obtained for oligomers 6e-l. Monomers 5a-d were not polymerized.
2906
Org. Lett., Vol. 12, No. 13, 2010

A number of cyclic and acyclic amines as well as O- and
S-nucleophiles were subjected to the established benzylation
protocol and were found to proceeed smoothly to afford the
desired benzylated products in excellent yields and purities
(Table 1). A number of monomeric analogues of OBP were
also prepared in good yields using several substituted benzyl
alcohols. Subjection of the monomers to the established
ROM polymerization protocol afforded the desired oligmeric
products in excellent yields as free-flowing white solids.
Interestingly, efforts toward production of monomeric phos-
phates 5a-d did not afford the desired products. This is
likely due to a combination of the substituent mesomeric
effect and/or eliminative degradation pathways of these
phosphates (Table 2). The corresponding oligomers 6e-l
were subjected to established benzylation conditions utilizing
morpholine as a test substrate and conveniently afforded the
desired benzylated products in moderate to good yields and
purities (Table 3).
Table 4. Benzylation of Benzothiaoxazepine-1,1-dioxides
SM
R1
R2
R3
R4
pdt
yield (%)a
9a
9a
9a
9b
9b
9c
9d
9d
4-Br
4-Br
4-Br
4-Br
4-Br
3-Cl
5-Cl
3-Cl
Ph
Ph
Ph
iBu
iBu
iBu
Me
Me
H
H
H
H
H
H
Ph
Ph
Bn
10a
10b
10c
10d
10e
10f
99
72
85
97
81
76
78
83
3,5-diMeO-Bn
4-F Bn
4-F Bn
2-Me Bn
4-Cl Bn
2-Me Bn
2-Me Bn
10g
10h
a Yields after filtration through a SiO2 SPE.
Table 3. Benzylation of Amines Using Various OBP Analogues
added to a THF solution containing benzothiaoxazepine-1,1-
dioxide (9a) in the presence of K2CO3 and Bu4NI and stirred
at 80 °C overnight. The resulting mother liquor was
precipitated from a Et2O/EtOAc mixture. Subsequent filtra-
tion employing a silica SPE cartridge, and evaporation of
solvent afforded the desired benzylated product 10a in
excellent yield and high purity. With this result in place,
sultams 9a-d were subjected to benzylation employing OBP
derivatives utilizing the conditions established above to afford
the desired products (10b-h) in good to excellent yields.
In conclusion, we have demonstrated the synthesis and
utilization of ROMP-based oligomeric phosphates for fa-
cilitated benzylation of cyclic amines and have applied it
toward simple diversification pathways in relevant scaffolds.
These oligomeric reagents are readily synthesized from
commercially available materials and are conveniently po-
lymerized and purified in a one-pot process affording pure
reagent on multigram scale. Efforts to widen the scope of
this reagent, improvement in synthesis and scale-up, and its
continued integration into diversity-oriented synthetic pro-
tocols is underway. The results of these endeavors will be
reported in due course.
Acknowledgment. This investigation was generously
supported by the National Institute of General Medical
Sciences (NIH P050-GM069663 and NIH-STTR R41
GM076765) with additional funds from the State of Kansas.
We would like to also thank Materia, Inc. for supplying
catalyst and helpful discussions.
Supporting Information Available: Detailed experimen-
tal procedures and tabulated 1H NMR, 13C NMR, 31P NMR,
FTIR, and mass data and 1H NMR spectra of crude products
obtained by the described benzylation method. This material
is available free of charge via the Internet at http://pubs.acs.org.
a Purities calculated using GC and further confirmed by 1H NMR.
b Despite their simplicity, each compound is classified as a NCE.
The 20-mer of OBP was tested on a select benzofused
sultam scaffold for benzylation (Table 4). The reagent was
OL1006604
Org. Lett., Vol. 12, No. 13, 2010
2907