Solid-phase synthesis of cleavable N-arylmaleimides: Applications in 1,3-dipolar cycloaddition and in thiol scavenging

Article abstract of DOI:10.1021/ol016533+

(matrix presented) An efficient solid-phase synthesis of polymer-supported N-arylmaleimides has been developed. Various N-arylmaleimidobenzoic acids (MBA) were elaborated onto Rink and SASRIN resins by reaction of the aniline precursors with maleic anhydride followed by facile cyclative dehydration of the resulting maleimic acids. Applications of these acid-cleavable MBA resins in the solid-phase synthesis of highly decorated pyrrolidines and as thiol scavengers are presented.

Full text of DOI:10.1021/ol016533+

ORGANIC
LETTERS
2001
Vol. 3, No. 22
3491-3494
Solid-Phase Synthesis of Cleavable
N-Arylmaleimides: Applications in
1,3-Dipolar Cycloaddition and in Thiol
Scavenging
Hamid R. Hoveyda1 and Dennis G. Hall*
Department of Chemistry, UniVersity of Alberta, Edmonton, AB, T6G 2G2 Canada
dennis.hall@ualberta.ca
Received August 3, 2001
ABSTRACT
An efficient solid-phase synthesis of polymer-supported N-arylmaleimides has been developed. Various N-arylmaleimidobenzoic acids (MBA)
were elaborated onto Rink and SASRIN resins by reaction of the aniline precursors with maleic anhydride followed by facile cyclative dehydration
of the resulting maleimic acids. Applications of these acid-cleavable MBA resins in the solid-phase synthesis of highly decorated pyrrolidines
and as thiol scavengers are presented.
Even though maleimides are highly prized substrates in
synthetic organic chemistry (as dienophiles, dipolarophiles,
and Michael acceptors), and although they find abundant
utility in a variety of biological applications,2 no reports on
the preparation of cleaVable polymer-supported N-substituted
maleimides have yet appeared in the literature (cf. Figure
1).3 The use of Friedel-Crafts reactions to attach a maleimide
moiety to unfunctionalized polystyrene, providing N-meth-
ylmaleimido polystyrene, has long been precedented in the
polymer chemistry literature4 and has recently been revisited
by Porco and co-workers.5,6 This approach, however, does
not readily lend itself to the preparation of cleaVable
maleimide resins. We became initially interested in the
preparation of acid-cleavable supported maleimides as part
of an effort to apply our previously reported tandem aza-[4
+ 2]/allylboration chemistry7 onto solid support. The po-
tential utility of supported maleimides in solid-phase organic
synthesis and/or as scavengers in parallel solution-phase
synthesis has prompted us to disclose their preparation. We
also report herein on applications of these cleavable resin-
supported maleimides in diastereoselective 1,3-dipolar cy-
cloaddition chemistry and thiol scavenging.
Our initial efforts were directed at synthesizing N-
aminoalkylmaleimides via dehydrative cyclization of N-
alkylmaleimic acid intermediates attached to trityl resin (1
f 2 in Scheme 1).8 The reaction of resin-bound amines with
maleic (or succinic) anhydrides cleanly afforded the desired
N-alkylmaleimic acids (or N-alkylsuccinamic acid). However,
all of the attempted solid-phase6 and solution-phase methods9
used for dehydrative cyclization of such an intermediate
(1) Current address: Ne´okimia Inc., 3001 12e Avenue Nord, Fleurimont
(Que´bec), J1H 5N4 Canada.
(2) See, for example: (a) Janda, K. D.; Ashley, J. A.; Jones, T. M.;
McLeod, D. A.; Schloeder, D. M.; Weinhouse, M. I. J. Am. Chem. Soc.
1990, 112, 8886. (b) Smyth, G. E.; Colman, R. F. J. Biol. Chem. 1991,
266, 14918. (c) Rusiecki, V. K.; Warne, S. A. Bioorg. Med. Chem. Lett.
1993, 3, 707. (d) Hermanson, G. T. Bioconjugate Techniques; Academic
Press: New York, 1996; p 148. (e) Seelig, B.; Keiper, S.; Stuhlmann, F.;
Ja¨schke, A. Angew. Chem., Int. Ed. 2000, 39, 4576.
(3) Most recently, a method to anchor maleimide to trityl resin was
reported: Barrett, A. G. M.; Boffey, R. J.; Frederiksen, M. U.; Newton, C.
G.; Roberts, R. S. Tetrahedron Lett. 2001, 42, 5579.
(6) For another preparation from aminomethyl polystyrene and maleic
anhydride using dehydrative cyclization, see: Rebek, J., Jr.; Gavin˜a, F. J.
Am. Chem. Soc. 1975, 97, 3453.
(7) Tailor, J.; Hall, D. G. Org. Lett. 2000, 2, 3715.
(4) Stevens, M. P.; Jenkins, A. D. J. Polym. Sci. 1979, 17, 3675.
(5) Wang, X.; Parlow, J. J.; Porco, J. A. Org. Lett. 2000, 2, 3509.
(8) For a comprehensive overview, see: Maleic Anhydride; Trivedi, B.
C.; Culberton, B. M.; Plenum Press: New York, 1982.
10.1021/ol016533+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/04/2001

N-Arylmaleimidobenzoic acids (MBA) are frequently
employed in the preparation of (maleimide) cross-linked
polymers.12 We decided to examine that chemistry for the
solid-phase synthesis of acid-cleavable MBA-conjugated
resins. To our satisfaction, this synthetic route (Scheme 2)
Scheme 2. General Route for the Preparation of
N-Arylmaleimidobenzoic Acid (MBA) Resinsa
Figure 1. Potential applications of polymer-supported maleimides
in solid-phase chemistry.
Scheme 1. Attempted Cyclative Dehydration Routes to
Cleavable Resin-Supported N-Alkylmaleimidesa
a (a) p-Nitrobenzoic acid (8 equiv), DIC (4 equiv), DMAP (cat.),
DMF, rt, 2 h (repeated twice). (b) SnCl2‚2H2O (20 equiv, 2 M in
anhydrous DMF), DMF. (c) Maleic anhydride (20 equiv), DMF,
rt, 6 h. (d) Ac2O (10 equiv), NaOAc (1 equiv), DMF, rt, 4 h. (e)
Wang resin: 90% TFA/CH2Cl2. SASRIN resin: 0.5% TFA/CH2Cl2.
a (a) H2N(CH2)6NH2 (50 equiv), THF, rt, 2 h. (b) Maleic
anhydride (20 equiv), CH2Cl2. (c) Conditions attempted at rt: (i)
Ac2O/NaOAc (cat.); (ii) DIC; (iii) DIC, DMAP; (iv) TEA; (v)
pyridine; (vi) HBTU; (vii) Ti(i-OPr)4; (viii) TMOF; (ix) TMOF,
DMAP; (x) SOCl2, pempidine; (xi) (COCl)2, pempidine.
indeed provides an efficient protocol for the attachment of
N-arylmaleimides onto acid-cleavable supports such as Wang
or SASRIN resins. For example, coupling of the readily
available p-nitrobenzoic acid (or substituted analogues) using
DIC/DMAP (cat.), followed by SnCl2 reduction of the nitro
group in 3, and the attendant coupling of the unmasked
aniline functionality to maleic anhydride cleanly furnished
the supported N-arylmaleimic acid 4. Dehydrative cyclization
of 4 was readily effected by treatment of the resin with acetic
anhydride (10 equiv) and sodium acetate (1 equiv) for 4 h
at room temperature, in anhydrous DMF, to obtain the
desired p-N-arylmaleimidobenzoic acid (p-MBA) resin 5
(Scheme 2).13 The efficiency of this procedure was monitored
by cleavage of resin samples with TFA/CH2Cl2 and analysis
of the resulting maleimide 6 by NMR and LCMS.14 It is
failed to cleanly furnish the resin-bound maleimide (see
footnote c in Scheme 1). Experimental conditions that
required acidic conditions or extensive heating periods at
highly elevated temperatures were not attempted (incompat-
ible with a trityl linker). Similarly, Mitsunobu coupling
between resin-bound alcohols10 and maleimide, as well as
milder variants of the Gabriel reaction11 to displace a resin-
immobilized primary mesylate were found to be ineffective.
(9) For examples of solution-phase synthesis of maleimides, see: (a)
Tawney, P. O.; Snyder, R. H.; Conger, R. P.; Leibbrand, K. A.; Stiteler, C.
H.; Williams, A. R. J. Org. Chem. 1961, 26, 15 and references therein. (b)
Hargreaves, M. K.; Pritchard, J. G.; Dave, H. R. Chem. ReV. 1970, 70, 439
and references therein. (c) Garner, P.; Ho, W. B.; Grandhee, S. K.; Youngs,
W. J.; Kennedy, W. O. J. Org. Chem. 1991, 56, 5893 and references therein.
(d) Braish, T. F.; Fox, D. E. Synlett 1992, 979. (e) Clevenger, R. C.;
Turnbull, K. D. Synth. Commun. 2000, 30, 1379.
(11) (a) Landini, D.; Rolla, F. Synthesis 1976, 389. (b) Sato, T.; Otera,
J. Synlett 1995, 336.
(12) (a) Stenzenberger, H. In Polyimides; Wilson, D., Stenzenberger, H.
D., Hergenrother, P. M., Eds.; Blackie: Glasgow, 1990; p 79. (b) Liu, F.
J.; Munukutta, S.; Levon, K.; Tesoro, G. J. Polym. Sci., Part A: Polym.
Chem. 1992, 30, 157 and references therein.
(10) (a) Walker, M. A. Tetrahedron Lett. 1994, 35, 665. (b) Walker, M.
A. J. Org. Chem. 1995, 60, 5352.
(13) In stark contrast, use of DIC/DMAP procedures for the cyclization
step was unsuccessful, giving a complex mixture of products.
3492
Org. Lett., Vol. 3, No. 22, 2001

noteworthy that by the same analytical criteria, the direct
attachment of preformed p-MBA (via ester or amide link-
ages) provided us with cleaved products of lower purity. The
corresponding isomeric m-MBA resin 7 and a bromo-
derivatized MBA resin (8) were also made to show the
generality of this approach.14 In principle, the phenyl ring
on these MBA resins could be further diversified by, for
instance, Suzuki or Heck coupling on brominated resin 8.
Maleimides have already found use in the solid-phase
synthesis of fused bicyclic pyrrolidines,15 most commonly
via the 1,3-dipolar cycloaddition16,17 of azomethine ylids
generated from R-aminoesters and aldehydes. To date,
however, because of the lack of methods to access cleaVable
resin-supported maleimides, another one of the highly
diversifiable building blocks has always been sacrificed as
the resin-immobilized component. For instance, Hamper and
co-workers opted to use the Mitsunobu coupling of substi-
tuted hydroxybenzaldehydes to immobilize the aldehyde
reagent onto the solid support.15a Hird and Bicknell, on the
other hand, took advantage of commercially available amino
acid loaded resins to access azomethine ylids.15b
method for the stereocontrolled synthesis of functionalized
pyrrolidines in solution phase (Scheme 3). Thus, an equi-
molar mixture of LiBr and DBU in dry THF (5-fold excess
relative to initial loading of resin), in the presence of the
Schiff base (10-fold excess) and the SASRIN p-MBA resin
5, furnished after cleavage (0.5% TFA in CH2Cl2) the syn-
endo diastereomer of the cycloadduct, as expected, after only
1 h at room temperature. The use of anhydrous conditions
was found necessary mainly to thwart the hydrolysis of the
resulting imide moiety. The mild conditions of Tsuge’s
N-metalation route employed herein (ambient temperature,
1 h) are in vivid contrast to the previously reported solid-
phase approaches (100-110 °C, 18-24 h).15a,b On the other
hand, the high diastereoselectivity obtained using such mild
conditions is well precedented in 1,3-dipolar cycloaddition
reactions both in solution and on solid phase. Our assignment
of the relative stereochemistries is consistent with that
reported in solution chemistry, resulting from the endo
addition of the maleimide to the syn-W (E,E-ylid) configu-
ration of the azomethine ylid, and is supported by NOE
difference studies.
A number of 1,3-dipolar cycloadducts (13, 14, 15) of the
respective SASRIN MBA resins (5, 7, 8) were prepared in
order to make a preliminary assessment of the scope and
limitations of our solid-phase synthetic strategy to substituted
pyrrolidines (Table 1). The general structure-reactivity
To explore the utility of our MBA resins, we chose to
study their usefulness in intermolecular 1,3-dipolar cyclo-
addition chemistry with azomethine ylids (Scheme 3). After
Scheme 3. 1,3-Dipolar Cycloaddition between Azomethine
Ylids of r-Iminoesters 11 and SASRIN MBA Resins 5, 7, and
8a
Table 1. Preparation of Substituted Pyrrolidines 13-15 from
11 and SASRIN MBA Resins (5, 7, 8) According to Scheme 3a
aldehyde
(Ar)
R-iminoester
product yieldb purityc
entry
(R1, R2)
(%)
(%)
(%)
1
2
3
4
5
6
7
8
9
C6H5
Leu (i-Bu, Me)
13a
13b
13c
13d
13e
13f
13g
13h
14a
15a
15b
85
50
95
80
65
80
>90
90
>80
>90
>90
>90
3,4,5-(MeO)C6H2 Leu (i-Bu, Me)
C6H5
3-NO2C6H4
C6H5
2-furyl
1,3,5-(Me)C6H2
C6H5
3-NO2C6H4
Tyr (p-HO-Bn, Et)
Phe (Bn, Et)
Phe (Bn, Et)
Phe (Bn, Et)
Ala (Me, Et)
His (CH2-4-Im, Et)
Phe (Bn, Et)
Phe (Bn, Et)
80
55
75
95
>90
>90
10 3-NO2C6H4
11 2-furyl
Phe (Bn, Et)
a Reactions were conducted according to Scheme 3 (typical scale 0.1-
0.5 g resin). See Supporting Information for detailed conditions. b Nonop-
timized weight yields of crude products, isolated as monotrifluoroacetate
1
salts after cleavage from the resin. c Estimated by integration of H NMR
a (a) Toluene, 80 °C, 1 h. (b) R-Iminoester (10 equiv), DBU (5
equiv), LiBr (5 equiv), SASRIN-MBA resin 5, 7, or 8 (1 equiv),
THF, rt, 1 h. (c) 0.5% TFA/CH2Cl2, rt, 1 h.
signals.
trends, based on the limited examples reported herein, may
be summarized as follows: (i) The cycloaddition reaction
examining a variety of Lewis acid/base combinations fol-
lowing the methods of Grigg16a and/or Tsuge,18 we opted
for Tsuge’s N-metalation route, which is an established
(16) For general reviews on 1,3-dipolar cycloaddition, see: (a) Grigg,
R. Chem. Soc. ReV. 1987, 16, 89. (b) Tsuge, O.; Kanemasa, S. AdV.
Heterocycl. Chem. 1989, 45, 231. (c) Padwa, A. Intermolecular 1,3-Dipolar
Cycloadditions. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. IV, p 1069.
(17) For other recent applications of 1,3-dipolar cycloaddition on solid
support, see: (a) Costero, A. M.; Pitarch, M.; Luz Cano, M. J. Chem. Res.,
Synop. 1994, 316. (b) Murphy, M.; Schullek, J. R.; Gordon, E. M.; Gallop,
M. A. J. Am. Chem. Soc. 1995, 117, 7029. (c) Kantorowski, E. J.; Kurth,
M. J. Mol. DiVersity 1996, 2, 207. (d) Hollinshead, S. P. Tetrahedron Lett.
1996, 37, 9157. (e) Peng, G.; Sohn, A.; Gallop, M. A. J. Org. Chem. 1999,
64, 8342.
(14) The resin loading was estimated by combustion analysis of the
nitrogen content on the resin, and the results indicated a loading in excess
of 90% in the cases of all three linkers reported herein. Estimated values
of resin loading and homogeneity of cleaved maleimides were also assessed
from nonoptimized weight yields after acidic cleavage (characterized by
NMR, and LCMS): p-MBA, 100%; m-MBA, 90%; Br-MBA, 70%).
(15) (a) Hamper, B. C.; Dukesherer, D. R.; South, M. S. Tetrahedron
Lett. 1996, 37, 3671. (b) Bicknell, A. J.; Hird, N. W. Biorg. Med. Chem.
Lett. 1996, 6, 2441.
Org. Lett., Vol. 3, No. 22, 2001
3493

dienes,5 and thiols in solution (cf. Figure 1). While the use
of a maleimide resin as a scavenger in the form of a
cycloaddition partner has garnered attention,5 its utility as a
thiol scavenger has not. Solid-support immobilized male-
imide moiety readily undergoes Michael addition with thiol
nucleophiles. Thus it functions as a thiol scavenger in
solution without generating any acidic byproducts, unlike the
case when solid-support immobilized alkylhalides are used
as scavengers. The reaction of three model sulfydryl com-
pounds (2-mercaptoethanol, thioacetic acid, thiophenol) with
a 2-fold excess of the Wang p-MBA resin 5 (1.3 mmol/g
loading) was found to be reasonably efficient, providing
quantitative thiol removal as observed by 1H NMR after 18
h (rt, chloroform). We expect that more efficient scavenger
resins (i.e., higher loading) could easily be prepared using,
for instance, a polyamine tether to increase the density of
maleimides on the resin.
Scheme 4. Scavenging of Sulfydryl Compounds with Wang
p-MBA Resin 5a
In conclusion, we have developed conditions for the first
general approach to the solid-phase synthesis of acid-
cleavable N-arylmaleimidobenzoic acid (MBA) resins. Such
a strategy can be used for more diversity-effective approaches
to combinatorial libraries of heterocycles using diastereose-
lective 1,3-dipolar cycloaddition chemistry. We have also
demonstrated the potential utility of maleimide resins for use
as “neutral” thiol scavengers.
a These experiments were conducted in deuterated chloroform
(rt), and the amount of thiol or thio acid left in solution was
quantified by integration of signals by H NMR.
1
is more sensitive to the steric bulk on the azomethine ylid
than the electronic factors, i.e., electron-rich and electron-
poor Schiff bases underwent the 1,3-dipolar cycloaddition
with comparable efficiency (entries 2 and 4), whereas the
sterically encumbered mesitaldehyde-derived Schiff base
(entry 7) failed to undergo the cycloaddition under the same
conditions. (ii) Amino acid building blocks with side chains
bearing an unprotected basic moiety, such as the imidazole
ring in histidine (entry 8), did not furnish clean cycloaddition
products under these conditions; those with an unprotected
acidic side chain (entry 3) did yield the desired cycloadduct,
albeit in lower purity.
Acknowledgment. This work was funded by the Natural
Sciences and Engineeering Research Council (NSERC) of
Canada and the University of Alberta.
Supporting Information Available: Experimental pro-
cedures for the synthesis of N-arylmaleimide resins, 1,3-
dipolar cycloadducts, and thiol scavenging; characterization
1
data (NMR, MS) along with copies of H and 13C NMR
spectra for pyrrolidines 13-15. This material is available
free of charge via the Internet at http://pubs.acs.org.
With the increased application of combinatorial synthetic
protocols in solution, there is also a greater need for various
scavengers and solid-support immobilized reagents.19 Ma-
leimide resins may be used in scavenging excess 1,3-dipoles,
OL016533+
(19) (a) Booth, R. J.; Hodges, J. C. Acc. Chem. Res. 1999, 32, 18. (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, 23, 3815. (c) Eames, J.; Watkinson, M.
Eur. J. Org. Chem. 2001, 1213.
(18) Tsuge, O.; Kanemasa, S.; Yoshioka, M. J. Org. Chem. 1988, 53,
1384.
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