Development of high-load, soluble oligomeric sulfonate esters via ROM polymerization: Application to the benzylation of amines

Article abstract of DOI:10.1021/ol049209y

The development of high-load, soluble oligomeric sulfonate esters, generated via ROM polymerization, and their utility in the facile benzylation of an array of amines is reported. These polymeric sulfonate esters exist as free-flowing powders, are stable

Full text of DOI:10.1021/ol049209y

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2657-2660
Development of High-Load, Soluble
Oligomeric Sulfonate Esters via ROM
Polymerization: Application to the
Benzylation of Amines
,‡
,†
Mianji Zhang,† Joel D. Moore,† 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 April 29, 2004
ABSTRACT
The development of high-load, soluble oligomeric sulfonate esters, generated via ROM polymerization, and their utility in the facile benzylation
of an array of amines is reported. These polymeric sulfonate esters exist as free-flowing powders, are stable at refrigerated temperatures, and
are readily dissolved in CH Cl2. Following the benzylation event, purification is attained via simple filtration, followed by solvent removal to
2
deliver the desired benzylated product in good to excellent yield and high purity.
The growing need for the rapid production of compounds
for screening has necessitated the development of facilitated
synthetic protocols whereby the science of synthesis and
purification are integrated. In this context, an array of
polymer-bound scavengers and reagents has appeared, ef-
fectively eliminating or circumventing the need for chro-
matographic purifications.1 Recent successes in multistep
total syntheses using almost exclusively immobilized reagents/
scavengers1e,2 are a testament to the power of this approach
whereby filtration was the sole purification protocol em-
ployed. Despite huge advances in this area, the need for
improvements in both resin-load capacity and reaction rates
continues to warrant the development of new and improved
immobilized reagents.
Soluble polymers,3 with differential solubility profiles,
have emerged as a means of exploiting solution-phase
reaction kinetics with all the advantages of their solid-phase
(1) (a) Regen, S. L.; Lee, D. P. J. Org. Chem. 1975, 40, 1669-1670.
(b) Kaldor, S. W.; Siegel, M. G.; Fritz, J. E.; Dressman, B. A.; Hahn, P. J.
Tetrahedron Lett. 1996, 37, 7193-7196. (c) Shuttleworth, S. J.; Allin, S.
M.; Sharma, P. K. Synthesis 1997, 1217-1239. (d) Booth, R. J.; Hodges,
J. C. Acc. Chem. Res. 1999, 32, 18-26. (e) 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. (f) 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 (g) van Heerbeek, R.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.:
Reek, J. N. H. Chem. ReV. 2002, 102, 3717-3756. (h) Yoshida, J.-I.; Itami,
K. Chem. ReV. 2002, 102, 3693-3716.
(2) (a) Baxendale, I. R.; Brusotti, G.; Matsuoka, M.; Ley, S. V. J. Chem.
Soc., Perkin Trans. 1 2002, 143-154. (b) Baxendale, I. R.; Ley, S. V.;
Piutti, C. Angew. Chem., Int. Ed. 2002, 41, 2194-2197. (c) Storer, R. I.;
Takemoto, T.; Jackson, P. S.; Ley, S. V. Angew. Chem., Int. Ed. 2003, 42,
2521-2525. (d) Parlow, J. J.; Flynn, D. L. Tetrahedron 1998, 54, 4013-
4031.
† University of Kansas.
‡ Neogenesis. Current address: Deciphera Pharmaceuticals LLC:
dflynn@deciphera.com.
10.1021/ol049209y CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/07/2004

counterparts. In addition, ring-opening metathesis polymer-
ization (ROMP)4 has surfaced as a means of facilitating
synthesis via the generation of designer polymers with
tunable properties and increased load levels when compared
with traditional resins. Our interest in the development of
facilitated synthetic protocols now leads us to report the
synthesis and utility of an array of high-load, soluble
oligomeric benzylating agents generated via ROM polym-
erization (Scheme 1).
to achieve the desired alkylation in a process termed “catch
and release”.8 In their protocol, arylsulfonyl chloride resins
having load values in the 1.1-1.4 mmol/g range were reacted
with a variety of alcohols to produce the desired insoluble
polymeric alkylating agents.
A logical starting point for our development of a high-
load, soluble benzylating agent was the oligomeric sulfonyl
chloride (OSC, 3) that we recently reported for homogeneous
amine scavenging.9 This OSC reagent is easily generated
from the ROM polymerization of 2-chlorosulfonyl-5-nor-
bornene (1) (derived from a simple Diels-Alder reaction)
utilizing the second-generation Grubbs catalyst 2. Following
the quenching process with ethyl vinyl ether, the OSC reagent
can be precipitated with ether to give a free-flowing powder
in excellent yield (Scheme 2).10
Scheme 1
Scheme 2
Benzylation continues to be one of the most commonly
used alkylation reactions in organic chemistry.5 Due to its
ease of incorporation and removal, the benzyl group also
serves as one of the most exploited protecting groups.6 In
addition, the hydrophobic, aromatic properties inherent to
the benzyl group make it an ideal diversity element in
combinatorial chemistry. When taken collectively, these
attributes logically point toward the development of an
immobilized benzylating agent. Surprisingly, to the best of
our knowledge, the literature is void of examples demon-
strating the use of immobilized benzylating agents.
We initially investigated an in situ benzylation protocol
that entailed reaction of the OSC reagent 3 with excess
triethylamine, followed by treatment with benzyl alcohol.
Subsequent addition of morpholine produced the benzylated
product 6a with high purity, albeit in low yield (30-35%).
Repeated attempts with this in situ protocol have yet to
improve the yield.
The area of developing immobilized alkylating agents was
first explored in 1996, when Roush and Hunt displaced a
polymer-bound alkylsulfonate with NaI to derive the respec-
tive alkyl halide in good yield.7 Reitz and co-workers
subsequently reported the use of a polystyrene resin-bound
sulfonyl chloride that was “activated” with a variety of
alcohols and further reacted in situ with a panel of amines
To circumvent this problem, we developed an improved
procedure whereby the oligomeric benzyl sulfonate esters
can be isolated and used in subsequent benzylation reactions.
Thus, reverse addition of a solution of OSC in CH2Cl2 at 0
°C into a stirred solution of benzyl alcohol (1.50 equiv) and
Et3N (1.0 equiv) in CH2Cl2 produced a homogeneous mixture
that was partitioned into diethyl ether to precipitate the
oligomeric sulfonate esters 4a-j as free-flowing powders
in quantitative yields with theoretical load values of ∼3.5
(3) 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. Eur.
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) 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
DiscoV. DeVel. 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, 2003; pp 361-402.
(5) Paquette, L. A. In Encyclopedia of Reagents for Organic Synthesis,
1st ed.; John Wiley and Sons: New York, 1995; pp 316-318. The most
common reagents to achieve this process are the benzylic bromides, which
present both safety and toxicity issues, most notably that they are severe
lachrymators.
(6) Greene, T. W.; Wuts, P. G. M. In ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons: New York, 1999; pp 76-86.
(7) Hunt, J. A.; Roush, W. R. J. Am. Chem. Soc. 1996, 118, 9998-
9999.
(8) Recently, the development of versatile arylsulfonyl chloride resins
as both scavenging resins and capture-release agents has been reported.
(a) Rueter, J. K.; Nortey, S. O.; Baxter, E. W.; Leo, G. C.; Reitz, A. B.
Tetrahedron Lett. 1998, 39, 975-978. (b) Baxter, E. W.; Rueter, J. K.;
Nortey, S. O.; Reitz, A. B. Tetrahedron Lett. 1998, 39, 979-982. (c)
Takahashi, T.; Ebata, S.; Doi, T. Tetrahedron Lett. 1998, 39, 1369-1372.
(d) For a review on polymer-supported arylsulfonyl chloride resin, see:
Huang, W.; He, B. Chin. J. React. Polym. (Engl.) 1992, 1, 61-70.
(9) (a) Moore, J. D.; Herpel, R. H.; Lichtsinn, J. R.; Flynn, D. L.; Hanson,
P. R. Org Lett. 2003, 5, 105-107. For a related ROMP-derived bis-acid
chloride oligomeric scavenger, see: (b) Moore, J. D.; Byrne, R. J.;
Vedantham, P.; Flynn, D. L.; Hanson, P. R. Org. Lett. 2003, 5, 4241-4244.
(10) We have previously found that there is good correlation between
the mol % Grubbs catalyst added and the Gaussian distribution of oligomers
formed, which we believe is the case with the OSC in Scheme 2. We have
made this reagent several times (i.e., the preparation and reactivity is
repeatable and consistently reliable). We normally obtain MALDI-TOF
and/or GPC data on all oligomers formed; however, both methods have
failed to give good results for this reactive oligomeric sulfonyl chloride
(OSC).
2658
Org. Lett., Vol. 6, No. 16, 2004

mmol/g. These oligomers are extraordinarily stable for long
periods of time and can thus be isolated and stored at
refrigerated temperatures.11 In addition, oligomers 4a-j are
readily dissolved in CH2Cl2 and can be added to a mixture
of Et3N and morpholine via cannulae, thus maintaining
homogeneity for optimal reaction kinetics. Furthermore, the
soluble aspects of this approach enable convenient dispensing
that could ultimately provide an enormous advantage in
parallel array synthetic protocols.
Scheme 4
We began our investigation with the simple benzylation
of morpholine (Table 1). Oligomers 4a-j were easily dis-
benzyl alcohol (15-20%). Presumably, these later entries
resulted from substantial hydrolysis of the benzylating
reagent during the reaction or the filtering process, thus
warranting care to preserve an anhydrous environment.
We next examined the benzylation of other secondary
amines using the simple benzylating agent 4a. Over the
course of this study, it was found that cyclic secondary
amines were the most successful in this process. The results
of the benzylation of these scaffolds, using the identical
procedure as above, led to the corresponding tertiary amines
7a-e in good yields and purities as outlined below in Table
2. The benzylated products were found to be only slightly
Table 1. Benzylation of Morpholine Results
starting
material
yield
(%)a
purity
(%)b
entry
R
product
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
6a
6b
6c
6d
6e
6f
6g
6h
6i
98
94
87
90
84
87
79
86
78
93
95
95
93
94
>90
92
79c
85c
82c
76c
o-Me
m-Me
p-Me
m-Br
o-NO2
p-NO2
p-tBu
p-Me, m-NO2
naphd
10
4j
6j
Table 2. Benzylation of Cyclic, Secondary Amines
a Yield of crude after filtration. b Purities were determined by GC and
confirmed by 1H NMR. c Substantial contamination with the corresponding
1
benzyl alcohol, as evident by H NMR. d R ) naph refers to a 1-naphthyl
sulfonate ester, not a naphthyl R group.
solved in CH2Cl2 and added to a mixture of 5.0 equiv of
Et3N and 1.0 equiv of morpholine, thus maintaining the
reaction kinetics of a homogeneous process.
After stirring for ∼1 h at 40 °C, these reaction mixtures
were subjected to a solution of dry ether, precipitating both
the “spent”, triethylammonium sulfonate oligomer 5 that was
generated over the course of the reaction and excess oligomer
4. This simple procedure effectively accomplished “phase-
trafficking” of the oligomers by facile manipulation of
solvent. Simple filtration using a fritted-glass funnel, fol-
lowed by solvent removal, delivered the desired benzylated
morpholines 6a-j in good to excellent yields and high purity
(Scheme 4). The benzylated products from entries 1-6 were
Scheme 3
a Yield of crude after filtration. b Purities were determined by GC and
confirmed by 1H NMR. All of the benzylated products are slightly
1
contaminated with benzyl alcohol, as evident by H NMR.
contaminated (<5%) with the benzyl alcohol, as evident by
1H NMR analysis.
found to be slightly contaminated (<5%) with the corre-
sponding benzyl alcohol, as evident by H NMR, while
entries 7-10 gave substantial amounts of the corresponding
Acyclic and aromatic amines were next investigated (Table
3), with benzylamine (entry 1) and anilines (entries 2 and
3) giving promising results. However, other acyclic amines
1
Org. Lett., Vol. 6, No. 16, 2004
2659

(Table 3, entries 1-6). Efforts are currently aimed at
extending this protocol to additional nucleophiles.
Table 3. Benzylation of Acyclic Amines and Other
Nucleophiles Using Oligomeric Sulfonate Ester 4a
In conclusion, we have demonstrated the first synthesis
and utilization of a ROMP-derived oligomeric benzylating
agent. These entities proved to be extremely efficient in the
benzylation of cyclic, secondary amines and with limited
success in the case of acyclic amines. Purification following
the alkylation reaction was carried out via simple precipita-
tion/filtration. Efforts to widen the scope of this reaction, as
well as its extension into the arena of combinatorial chem-
istry, are underway. The results of these endeavors will be
reported in due course.
nucleophile
(starting
material)
expected
product 8
product
entry
distributiona
1
2
3
4
BnNH2
PhNHMe
PhNH2
Bn2NH 8a Bn3N 8b 87% (8a ), 12% (8b)
PhN(Me)Bn 8cb
PhNHBn 8d
Ph2NBn 8e
93% (8c), 6% (BnOH)
87% (8d ), 4% (PhNBn2)
only starting material
recovered
Ph2NH
5
6
Et2NH
Bn2NH
Et2NBn 8f
Bn3N 8b
no benzylation
27% (8b), 71% (Bn2NH),
2% (BnOH)
7
8
p-NO2PhOH
p-NO2PhOBn 8g
only starting material
recovered
CH3(CH2)11SH CH3(CH2)11SBn 8h only starting material
recovered
Acknowledgment. This investigation was generously
supported by partial funds provided by the National Science
Foundation (NSF Career 9984926), the University of Kansas
Research Development Fund, and the NIH Center of Excel-
lence in Combinatorial Methodologies and Library Develop-
ment (KU-CMLD, NIH 1P50 GM069663-01) with additional
funds from the State of Kansas. The authors thank Neogen-
esis Pharmaceuticals, Inc., for providing generous postdoc-
toral support (M.Z.) and Materia, Inc., for supplying catalyst
and helpful discussions.
a Determined by GC/MS. b Yield of crude after filtration was 81%. For
1H NMR, 13C NMR, and mass data of 8c, see Table 1 in Supporting
Information.
were more problematic (Table 3, entries 4-6) in producing
the desired benzylated amines. In addition, other nucleophiles
such as p-nitrophenol (entry 7) and 1-dodecanethiol (entry
8) also failed. We feel that nucleophilicity and/or steric
effects are the primary factors in these benzylations. This
fact is supported by the success of all cyclic amines (Tables
1 and 2) versus their acyclic secondary amino counterparts
Supporting Information Available: Detailed experi-
mental procedures, tabulated 1H NMR, 13C NMR, and mass
1
(11) We found that the stability of the oligomeric sulfonate esters is
directly affected by the electronic influence of the aromatic substituent.
For example, benzyl alcohols containing a methoxy group at either the ortho
or para position generated unstable oligomers. This is attributed to the strong
electron-donating ability of this substituent that could effectively displace
the sulfonate and react immediately with adventitious water present.
data, and H NMR spectra of crude products obtained by
the described successful benzylation method. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL049209Y
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Org. Lett., Vol. 6, No. 16, 2004