Click"-Capture, ring-opening metathesis polymerization (ROMP), release: Facile triazolation utilizing romp-derived oligomeric phosphates

Article abstract of DOI:10.1021/ol200430c

Soluble, high-load ring-opening metathesis polymerization (ROMP)-derived oligomeric triazole phosphates (OTP) are reported for application as efficient triazolating reagents of nucleophilic species. Utilizing a "Click"- capture, ROMP, release protocol, th

Full text of DOI:10.1021/ol200430c

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2038–2041
“Click”-Capture, Ring-Opening
Metathesis Polymerization (ROMP),
Release: Facile Triazolation Utilizing
ROMP-Derived Oligomeric Phosphates
Toby R. Long,† Saqib Faisal,†,‡ Pradip K. Maity,† Alan Rolfe,† Ryan Kurtz,†
Sarra V. Klimberg,† Muhammad-Rabbie Najjar,† Fatima Z. Basha,‡ and Paul R. Hanson*,†
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence,
Kansas 66045, United States, 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,
and H. E. J. Research Institute of Chemistry, International Center for Chemical and
Biological Science, University of Karachi, Karachi, Pakistan
phanson@ku.edu
Received February 16, 2011
ABSTRACT
Soluble, high-load ring-opening metathesis polymerization (ROMP)-derived oligomeric triazole phosphates (OTP) are reported for application as
efficient triazolating reagents of nucleophilic species. Utilizing a “Click”-capture, ROMP, release protocol, the efficient and purification-free, direct
triazolation of N-, O-, and S-nucleophilic species was successfully achieved. A variety of OTP derivatives were rapidly synthesized as free-flowing
solids on a multigram scale from commercially available materials.
Rapid access to collections of diverse molecules in
desirable quantities and purity for high-throughput
screening is an important challenge in drug discovery. In
this regard, methods that integrate synthesis and purifica-
tion have become powerful tools in the arena of facilitated
synthesis.1,2 This has been driven in recent years by the
development of an array of polymer-bound reagents and
scavengers for utilization in streamlined protocols to ac-
cess small molecule libraries.2 Despite huge advances
in this area, limitations in nonlinear reaction kinetics
(heterogeneous reactions), low resin-load capacities,
means of distributing reagents, and solution phase auto-
mation technology continue to warrant the development
ofdesignerpolymers for libraryproduction.3 Tothiseffect,
† University of Kansas.
‡ University of Karachi.
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r
10.1021/ol200430c
Published on Web 03/24/2011
2011 American Chemical Society

a variety of reagents and scavengers possessing tunable
properties have emerged from ring-opening metathesis
polymerization (ROMP) technology.4À6 We herein report
the development of a new ROMP-derived oligomeric
triazole phosphate (OTP) for application as a soluble,
efficient triazolating reagent of nucleophilic species. Over-
all, these reagents are free-flowing solids that are easy to
handle, nontoxic, soluble, and air stable. In addition, they
are easily stored long-term at room temperature and are
readily prepared, vide infra, from commercially available
starting materials on a multigram scale.
The development of new methodolgies for the diversifi-
cation of biologically interesting core scaffolds with func-
tional handles is of paramount importance. In this regard,
triazoles and their derivatives have demonstrated a wide
variety of biological activity, with many reports focusing
on antifungal activity.7 Despite this activity, the utilization
of solution phase or immobilized reagents to directly
triazolate nucleophilic species in a one-step protocol has
been limited to reports of a two-step, one-pot propargyla-
tion-click protocol.8
oligomeric benzyl phosphate (OBP) as an efficient benzy-
lating reagent.10 We now report the synthesis of ROMP-
derived triazolating reagents (OTP) for application in
purification-free diversifications of nucleophilic species
using the title method, termed “Click”-Capture, ROMP,
Release. This method utilizes a propargyl-tagged norbor-
nenyl-phosphate to capture an azide in a classical “click”
reaction, followedby ROM polymerization to generate the
desired soluble oligomeric triazole reagent (OTP) 4. Sub-
sequent release via SN2 displacement with nucleophilic
species yields triazolated products along with the spent
oligomeric phosphate that is readily sequestered via pre-
cipitation (Figure 1).
Oligomeric and polyphosphates are ideal immobilized
leaving groups due to the inherint pKa, stability and innate
leaving group properties of phosphate anions.9À11 Re-
cently, we reported the generation and application of
Figure 1. Reaction of oligomeric triazole phosphate (OTP) 4.
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2011, 1, 4–7. (b) Maity, P.; Rolfe, A.; Samarakoon, T. B.; Faisal, S.;
The synthesis of the oligomeric triazole phosphate bear-
ing a 4-MeOPh group, OTP 4a, starts with the exonorbor-
nenyl tagged(Nb-tagged) phosphonyl chloride1 utilizedin
the synthesis of previously reported ROMP-derived ben-
zylating reagent OBP.10,12 Phosphorylation of propargyl
alcohol with Nb-tagged phosphonyl chloride 1, followed
by a “Click”-capture event of the corresponding azide,
yields the desired monomer 3a in an efficient fashion.
ROM polymerization of monomer 3a was achieved with
RuCl2(PCy3)2dCHPh (cat. A), followed by basic workup
€
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Hanson, P. R. Tetrahedron Lett. 2008, 49, 4553–4555. (e) Zhang, M.;
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Roberts, R. S. J. Comb. Chem. 2005, 7, 21–32. (g) Harned, A. M.;
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Scheme 1. Synthesis of Oligomeric Triazole Phosphate (OTP) 4a
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Org. Lett., Vol. 13, No. 8, 2011
2039

utilizing the Pederson protocol.13,14 Precipitation via drop-
wise addition into anhydrous Et2O afforded the corre-
sponding oligomeric triazole phosphate (OTP20) 4a as a
free-flowing white solid possessing a theoretical load of 2.4
mmol/g (Scheme 1).
In addition to phenols, thiophenols (Table 1, entry 5) and a
variety of amines (Table 1, entries 6À10) were successfully
utilized to release the corresponding triazole in >90%
Table 2. Synthesis of Various OTP Analogues 4
Scheme 2. Triazolation of 2,4-Cl-PhOH Utilizing OTP 4a
monomer
R1
pdt
yield (%)a
3a
3b
3c
3d
3e
3f
4-OMe-Ph
4-Me-Ph
2-Me-Ph
4-Cl-Ph
4a
4b
4c
4d
4e
4f
82
88
77
71
74
73
70
89
56
Investigation into the utilization of OTP 4a as a direct
triazolating reagent was next studied using reaction con-
ditions reported for the application of OBP.10 After opti-
mization of reaction conditions for the triazolation of 2,4-
dichlorophenol utilizing OTP 4a, the corresponding tria-
zole ether, 5a, was isolated in excellent yield (99%) and
crude purity (>90%) using simple filtration through a
Celite SPE (Scheme 2).
4-F-Ph
4-CF3-Ph
Cylohexyl
4-Br-Ph
Furfuryl
3g
3h
3i
4g
4h
4i
a Yields corresponding to metathesis of corresponding monomers.
Table 1. Triazolation of N-, O-, and S-Nucleophiles Using
OTP20 4aa
Table 3. Triazolation Utilizing OTP Derivatives 4aÀga
entry
nucleophile
OTP
pdt
yield (%)b
1
naphthalene-1-ol
4a
4b
4c
4d
4e
4f
6a
6b
6c
6d
6e
6f
72
90
55
68
70
65
49
62
52
63
51
50
60
66
2
naphthalene-1-ol
3
naphthalene-1-ol
entry
nucleophile
2,4-Cl-PhOH
pdt
yield (%)b
4
naphthalene-1-ol
5
naphthalene-1-ol
1
2
5a
5b
5c
5d
5e
5f
98
92
90
69
60
72
75
95
88
62
6
naphthalene-1-ol
4-F-PhOH
4-tBu-PhOH
7
naphthalene-1-ol
4g
4a
4b
4c
4d
4e
4f
6g
6h
6i
3
8
N-ethylnaphthalen-1-amine
N-ethylnaphthalen-1-amine
N-ethylnaphthalen-1-amine
N-ethylnaphthalen-1-amine
N-ethylnaphthalen-1-amine
N-ethylnaphthalen-1-amine
N-ethylnaphthalen-1-amine
4
naphthalene-1-ol
4-SMe-PhSH
9
5
10
11
12
13
14
6j
6
morpholine
6k
6l
7
thiomorpholine
1-phenylpiperazine
indoline
5g
5h
5i
8
6m
6n
9
4g
10
N-ethylnaphthalen-1-amine
5j
a OTP 4aÀg utilized as a 20-mer. b Purities >90% observed for all
a OTP 4a utilized as a 20-mer. b Purities >90% observed for all
reactions using both GC and 1H NMR.
reactions using both GC and 1H NMR.
The application of OTP 4a as an efficient triazolating
reagent was extended to a variety of N-, O-, and S-
nucleophilic species (Table 1). Initially, a variety of phenols
were utilized (Table 1, entries 1À3) though reduced yields
were observed for sterically hindered napthalene-1-ol.
crude purity. Building on the success of OTP 4a, a variety
of additional OTP derivatives 4bÀ4i were synthesized as
free-flowing powders on a gram scale from ROM poly-
merization of their corresponding monomers utilizing cat.
A (Table 2).
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Org. Lett., Vol. 13, No. 8, 2011

With a variety of OTP 4 derivatives in hand, the triazola-
tion of both naphthalene-1-ol and N-ethylnaphthalen-1-
amine with OTP derivatives 4aÀg was investigated (Table
3). All reactions proceeded with good yields with >90%
crude purity after Celite SPE to remove the spent oligomer.
In conclusion, we have developed and demonstrated the
synthesis and utilization of oligomeric triazole phosphates
for direct triazolation of N-, O- and S-nucleophilic species
in a “Click”-capture, ROMP, release protocol. These
oligomeric reagents are readily synthesized on a multigram
scale from commercially available materials as soluble,
high-load, free-flowing powders. The application of OTP
in the diversification of core scaffolds for the synthesis of
diverse collections of small molecules is underway and will
be reported in due time.
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 the metathesis catalyst and helpful discussions.
Supporting Information Available. Detailed experimen-
1
tal procedures and tabulated H NMR, 13C NMR, 31P
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1
NMR, FTIR, and mass data and H NMR spectra of
products obtained by the described methods. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
Org. Lett., Vol. 13, No. 8, 2011
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