Polymer-supported O-alkylisoureas: Useful reagents for the O-alkylation of carboxylic acids

Article abstract of DOI:10.1021/jo049239e

Polymer-supported O-alkylisoureas were prepared by reaction of an alcohol with a polymer-supported carbodiimide under copper(II) catalysis. These reagents were used to transform carboxylic acids into the corresponding methyl, benzyl, allyl, and p-nitrobenzyl esters in a highly chemoselective manner in high yields and in very high purity after simple resin filtration and solvent evaporation. The reactions could be carried out using both conventional or microwave heating, with reaction times as short as 3-5 min in the latter case, without compromising yield, purity, or chemoselectivity. Unfortunately, the corresponding solid-supported tert-butyl isoureas could not be prepared.

Full text of DOI:10.1021/jo049239e

P olym er -Su p p or ted O-Alk ylisou r ea s: Usefu l Rea gen ts for th e
O-Alk yla tion of Ca r boxylic Acid s
Stefano Crosignani,†,‡ Peter D. White,§ and Bruno Linclau*,†
Combinatorial Centre of Excellence, School of Chemistry, University of Southampton,
Highfield, Southampton SO17 1BJ , United Kingdom, and Novabiochem, Merck Biosciences Ltd.,
Padge Road, Beeston NG9 2J R, United Kingdom
bruno.linclau@soton.ac.uk
Received May 5, 2004
Polymer-supported O-alkylisoureas were prepared by reaction of an alcohol with a polymer-
supported carbodiimide under copper(II) catalysis. These reagents were used to transform carboxylic
acids into the corresponding methyl, benzyl, allyl, and p-nitrobenzyl esters in a highly chemoselective
manner in high yields and in very high purity after simple resin filtration and solvent evaporation.
The reactions could be carried out using both conventional or microwave heating, with reaction
times as short as 3-5 min in the latter case, without compromising yield, purity, or chemoselectivity.
Unfortunately, the corresponding solid-supported tert-butyl isoureas could not be prepared.
In tr od u ction
Polymer-assisted solution-phase protocols for ester
formation are typically illustrated by the use of im-
mobilized scavengers4 or immobilized catalysts.5 The use
of solid-supported carbodiimides was reported only for
the esterification of carboxylic acids with the reactive
N-hydroxysuccinimide and perfluorophenol.6 The use of
polymer-supported sulfonyl chlorides and sulfonyl-3-
nitro-1H-1,2,4-triazolide was reported for the esterifica-
tion of carboxylic acids with alcohols in the presence of a
base (N-methylimidazole).7 The use of solid-supported
alkylsulfonates as “alkylating resins” was only reported
for the synthesis of secondary and tertiary amines,
thioethers, and N-alkylimidazoles.8
It was not until 2001 that the first polymer-supported
reagents capable of alkylating a carboxylic acid without
requiring any other co-reagent appeared, when Bra¨se and
Rademann independently described the efficient reaction
of immobilized triazenes with carboxylic acids to give the
corresponding ester products (Scheme 1a).9 High yields
and purities were obtained, and the reaction appeared
to be highly chemoselective. These polymer-supported
triazenes were initially developed by Bra¨se as “traceless”
linkers for solid-phase organic chemistry (SPOS).10 The
During the past few years, research on the preparation
and use of polymer-supported reagents has received
renewed interest.1 The properties of these reagents
(facilitated workup, reduced use of conventional purifica-
tion techniques, ease of application to robotic equipment)
make them ideal for the preparation of solution-phase
libraries. Additionally, Ley and co-workers have demon-
strated that polymer-supported reagents and scavengers
can also be successfully employed for the total synthesis
of complex natural products.2 An impressive illustration
in this respect was the synthesis of epothilone C, achieved
in 29 overall steps (17 steps for the longest linear
sequence), and which involved only one purification by
flash chromatography, to eliminate an unwanted minor
diastereoisomer, in the very last step.2a The usefulness
of polymer-supported reagents was further illustrated by
a successful application in which a library of histone
deacetylase inhibitors was synthesized in four to five
steps in a fully automated fashion.3
* To whom correspondence should be addressed. Fax: +44 23 8059
6805.
† University of Southampton.
‡ Current address: Serono Pharmaceutical Research Institute, 14
Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland.
§ Novabiochem.
(4) (a) Gayo, L. M.; Suto, M. J . Tetrahedron Lett. 1997, 38, 513-
516. (b) Warmus, J . S.; Ryder, T. R.; Hodges, J . C.; Kennedy, R. M.;
Brady, K. D. Bioorg. Med. Chem. Lett. 1998, 8, 2309-2314.
(5) (a) Kabaza, K. G.; Chapados, B. R.; Gestwicki, J . E.; McGrath,
J . L. J . Org. Chem. 2000, 65, 1210-1214. (b) Cainelli, G.; Menescalchi,
F. Synthesis 1975, 723-724.
(1) Reviews: (a) Flynn, D. L.; Berk, S. C.; Makara, G. M. Curr. Opin.
Drug Discovery Dev. 2002, 5, 580-593. (b) Eames, J .; Watkinson, M.
Eur. J . Org. Chem. 2001, 7, 1213-1224. (c) Kirschning, A.; Monen-
schein, H.; Wittenberg, R. Angew. Chem., Int. Ed. 2001, 40, 650-679.
(d) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; J ackson, 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.
(6) Adamczyk, M.; Fishpaugh, J . R.; Mattingly, P. G. Tetrahedron
Lett 1995, 36, 8345-8346.
(7) (a) Zander, N.; Frank, R. Tetrahedron Lett. 2001, 42, 7783-7785.
(b) Zander, N.; Gerhardt, J .; Frank, R. Tetrahedron Lett. 2003, 44,
6557-6560.
(2) (a) Storer, R. I.; Takemoto, T.; J ackson, P. S.; Ley, S. V. Angew.
Chem., Int. Ed. 2003, 42, 2521-2525. (b) MacCoss, R. N.; Brennan, P.
E.; Ley, S. V. Org. Biomol. Chem. 2003, 1, 2029-2031. (c) Lee, A.-L.;
Ley, S. V. Org. Biomol. Chem. 2003, 1, 3957-3966. (d) Baxendale, I.
R.; Davidson, T. D.; Ley, S. V.; Perni, R. H. Heterocycles 2003, 60,
2707-2715.
(8) Rueter, J . K.; Nortey, S. O.; Baxter, E. W.; Leo, G. C.; Reitz, A.
B. Tetrahedron Lett. 1998, 39, 975-978.
(9) (a) Pilot, C.; Dahmen, S.; Lauterwasser, F.; Bra¨se S. Tetrahedron
Lett. 2001, 42, 9179-9181. (b) Rademann, J .; Smerdka, J .; J ung, G.;
Grosche, P.; Schmid, D. Angew. Chem., Int. Ed. 2001, 40, 381-385.
(c) Erb, B.; Kucma, J .-P.; Mourey, S.; Struber, F. Chem. Eur. J . 2003,
9, 2582-2588.
(3) Vickerstaffe, E.; Warrington, B. H.; Ladlow, M.; Ley, S. V. Org.
Biomol. Chem. 2003, 1, 2419-2422.
10.1021/jo049239e CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/05/2004
J . Org. Chem. 2004, 69, 5897-5905
5897

Crosignani et al.
SCHEME 1. Solid -Su p p or ted Syn th esis of Ester s by (a ) th e Meth od of Br a1se a n d Ra d em a n n a n d (b) Ou r
Isou r ea -Med ia ted Meth od
SCHEME 2. Tr a d ition a l Syn th esis of P olym er -Su p p or ted Ca r bod iim id e 3
solid-supported triazenes were synthesized from solid-
supported diazonium salt by reaction with a primary
amine.
Resu lts a n d Discu ssion
Syn th esis of P olym er -Su p p or ted Ca r bod iim id e 3.
The synthesis of the polymer-supported O-alkyliso-
urea reagents was achieved in one step from polymer-
supported carbodiimide 3. Though 3 is commercially
available, and as such was successfully used for our
purposes, in-house prepared solid-supported carbodiimide
was mostly employed, as it could be easily obtained from
the cheaper aminomethylpolystyrene resin 5. In addition,
it was noted that esterification reactions with polymer-
supported isourea reagents derived from in-house pre-
pared carbodiimide resin tended to give rise to products
of higher purity, which was attributed to different
gradations of impurity leaching.
Several triazene resins were prepared (including meth-
yl, n-butyl, benzyl, and tert-butyl derivatives) starting
from the appropriate amines. Although the reactions of
most of these reagents with carboxylic acids gave the
corresponding esters in high yields, tert-butyltriazene
resin was not effective for the transformation of carbox-
ylic acids into tert-butyl esters. More recently, an im-
proved synthesis of polymer-supported triazenes was
reported starting from unfunctionalized polystyrene resin,
and the scope of this type of polymer-supported reagents
for the esterification of carboxylic acids was further
demonstrated.9c
The preparation of 3 (Scheme 2) has been described in
the literature.12 Aminomethylpolystyrene 5 was reacted
with cyclohexyl isocyanate to form the resin-bound urea
derivative 6, which was subsequently converted to the
corresponding carbodiimide 3. On an industrial scale, the
dehydration reaction is executed by using p-toluene-
sulfonyl chloride and triethylamine. However, as it was
suspected that this particular method was associated
with the generation of impurities, other dehydration
methods were investigated.
Many methods are known for the dehydration of ureas
to give carbodiimides (in the solution phase).13 Surpris-
ingly, many of these dehydration methods failed to
achieve carbodiimide formation on the solid-support
(Table 1). Good results were obtained with Ph3P‚Br2 and
excess base, though the reaction was found not to be
reproducible.
Subsequently, we have reported an alternative ap-
proach toward esterification reactions using immobilized
reagents based on solid-supported O-alkylisoureas 4
(Scheme 1b).11 The isourea resins were synthesized from
a solid-supported carbodiimide (Scheme 1b) by reaction
with an alcohol. Subsequent reaction with a carboxylic
acid gave the corresponding methyl, allyl, and benzyl
esters in high yields and purities, and the process also
displayed excellent chemoselectivity.
Both approaches displayed in Scheme 1 have the
advantage that the alkylating resins 2 and 4 can be
purified by washing before the carboxylic acid is added.
We report here a full account of the synthesis, optimi-
zation, and characterization of solid-supported isoureas
(O-methyl, O-allyl, O-benzyl, O-p-nitrobenzyl, and O-2-
(trimethylsilyl)ethyl) and their reaction with carboxylic
acids, with both steps investigated under conventional
thermal heating and under microwave heating condi-
tions. A scavenging protocol is developed for potential
parallel synthesis applications. We also report on an
optimized procedure for the synthesis of polymer-
supported carbodiimide 3.
While these studies were in progress, the successful
conversion of polymer-supported ureas to carbodiimides
using dehydrating reagents such as the Burgess reagent
(12) Weinshenker, N. M.; Shen, C. Tetrahedron Lett. 1972, 13,
3281-3284.
(13) (a) Newman, M.; Boden, H. J . Org. Chem. 1961, 26, 2525-2528.
(b) Bestmann, H.-J .; Lienert, J .; Mott. Liebigs Ann. Chem. 1968, 718,
24-32. (c) Appel, R.; Kleinstu¨ck, R.; Ziehn, K.-D. Chem. Ber. 1971,
104, 1335-1336. (d) Palomo, C.; Ramon, M. Bull. Soc. Chim. Fr. 1981,
361-364. (e) J a´szay, Z. M.; Petneha´zy, I.; To¨ke, L.; Szaja´ni, B.
Synthesis 1987, 520-523. (f) Yamamoto, N.; Isobe, M. Chem. Lett.
1994, 2299-2302. (g) Sclama, T.; Gouverneur, V.; Mioskowski, C.
Tetrahedron Lett. 1996, 37, 7047-7048. (h) Barvian, M. R.; Showalter,
H. D. H.; Doherty, A. M. Tetrahedron Lett. 1997, 38, 6799-6802.
(10) Brase, S.; Enders, D.; Koberling, J .; Avemaria, F. Angew. Chem.,
Int. Ed. 1998, 37, 3413-3415.
(11) (a) Crosignani, S.; White, P. D.; Linclau, B. Org. Lett. 2002, 4,
1035-1037. (b) Crosignani, S.; White, P. D.; Linclau, B. Org. Lett. 2002,
4, 2961-2963. (c) Crosignani, S.; White, P. D.; Steinauer, R.; Linclau,
B. Org. Lett. 2003, 5, 853-856. (d) Crosignani, S.; Launay, D.; Linclau,
B.; Bradley, M. Mol. Divers. 2003, 7, 203-210.
5898 J . Org. Chem., Vol. 69, No. 18, 2004

Polymer-Supported O-Alkylisoureas
TABLE 1. Deh yd r a tion of P olym er -Su p p or ted Ur ea 6
SCHEME 3. Micr ow a ve-Assisted Syn th esis of
P olym er -Su p p or ted O-Meth ylisou r ea 4a
dehydrating
agent
carbodiimide
formation
base
SCHEME 4. Attem p ted Micr ow a ve-Assisted
Syn th esis of P olym er -Su p p or ted O-Ben zylisou r ea
4b a n d Th er m a l-In d u ced Con ver sion of 4b to 7
SOCl2
SOCl2
PBr3
PBr3
(PhO)P(O)Cl2
Ph3P.Br2
CBr4 + Ph3P
Et3N
DBU
Et3N
DBU
Et3N
Et3N
Et3N
no
no
no
no
no
yes
yes
or with CBr4/Ph3P/Et3N was reported.14 Though it was
concluded that the best results were observed with the
Burgess reagent, we decided against using this method
as its cost was too high for large-scale preparations.
Because no experimental details were provided (reagent
equivalents, reaction times), it was decided to reinves-
tigate the CBr4-mediated method, and it was found that
the dehydration was successfully accomplished using 3
equiv of CBr4 and Ph3P and 9 equiv of Et3N overnight in
CH2Cl2.
parent. Although the carbodiimide band disappeared
from the IR spectrum and the isourea band became
visible, two strong bands were also present at 1640 and
1555 cm-1, indicating the presence of a urea group. When
the resin thus obtained was resubmitted to further
heating in the absence of benzyl alcohol using THF as
solvent, an increase of the urea bands at the expense of
the isourea band was observed. Though this experiment
indicated that a transformation of the O-benzylisourea
to an immobilized urea species as shown in Scheme 4
was occurring, we did not observe a similar process when
heating N,N′-diisopropyl-O-benzylisourea in a homoge-
neous solution in THF under otherwise identical condi-
tions. The structure of 7 is suggested solely based on IR
analysis.
Hence, the formation of the solid-supported isourea
reagent was reinvestigated under copper catalysis, with
the aim of developing conditions at room temperature.
Using copper(II) triflate as Lewis acid (50 mol %), which
has a higher solubility compared to CuCl in organic
solvents, stirring resin 3 in a 1:1 mixture of MeOH/THF
overnight led to the formation of a resin whose IR did
not show any carbodiimide band. However, the IR of the
resin did not match that of 4a previously prepared, nor
was the resin efficient in effecting ester formation. The
green color of the resin beads was indicative of the
presence of significant quantities of copper catalyst still
attached to the resin, which was confirmed by the
fact that addition of the resin to a carboxylic acid solu-
tion resulted in a pale blue color. At this point we
searched for a more effective procedure to remove the
copper species from the resin. Simple solvent washings
did not have any effect, nor washing with various
primary/tertiary amines. However, when a solution of
tetramethyl ethylenediamine (TMEDA) in CH2Cl2 was
used, the mixture immediately became dark blue
(Figure 2), evidencing formation of a Cu(II)-TMEDA
complex.
It should be noted that repeated resin washings were
required to remove all of the triphenylphosphine oxide
byproduct.
Syn th esis of th e P olym er -Su p p or ted O-Alk yliso-
u r ea s. Following the established procedure for the
synthesis of O-alkylisoureas from carbodiimides and
alcohols under CuCl catalysis,15 the synthesis of the
polymer-supported O-methylisourea was initially at-
tempted in a similar fashion. However, these initial
experiments were not successful, and it was decided to
investigate a method, already described in 1899,16 where
O-alkylisoureas could be formed simply by heating a
mixture of neat carbodiimide and an alcohol. Applied to
the formation of polymer-supported O-methylisourea, this
would require heating resin 3 in methanol as solvent.
This was a major obstacle in transferring this method
for our purposes, given the well-known inability of
methanol to swell polystyrene-type resins without which
no reaction could be expected within the beads. However,
the polarity of a solvent decreases significantly at high
temperature, and it was indeed demonstrated that
methanol could be used as solvent for polystyrene-based
solid-phase chemistry employing microwave induced
heating.17 In the event, it was found that heating resin
3 for 70 min at 135 °C under microwave irradiation
(Scheme 3) resulted in complete conversion of the car-
bodiimide to O-methylisourea. The transformation was
easily monitored by IR (Figure 1) through the disappear-
ance of the carbodiimide band at 2117 cm-1 and the
development of two characteristic isourea bands at 1663
and 1332 cm-1. Purification of the obtained resin was
easily achieved by filtration and two CH2Cl2 wash cycles.
However, when resin 3 was heated with benzyl alcohol,
the limitations of this preparation method became ap-
After three washes, the diamine solution remained
colorless (Figure 2), indicating that all copper species had
been removed, and subsequent washings to remove any
traces of TMEDA followed by drying gave a resin whose
IR spectrum was identical to the authentic sample.
(14) Lange, U. E. W. Tetrahedron Lett. 2002, 43, 6857-6860.
(15) Mathias, L. J . Synthesis 1979, 561-576.
(16) Dains, F. B. J . Am. Chem. Soc. 1899, 21, 136-192.
(17) Westman, J . Org. Lett. 2001, 3, 3745-3747.
J . Org. Chem, Vol. 69, No. 18, 2004 5899

Crosignani et al.
F IGURE 1. IR spectra of carbodiimide resin 3 (top) and isourea resin 4a (bottom).
Although CuCl could be used to efficiently catalyze the
isourea formation on solid-support instead of Cu(OTf)2,
the TMEDA-based washing procedure in this case failed
to remove all the copper species from the resin.
With a suitable washing process established, we next
optimized the reaction process. In the event, using only
7 mol % of Cu(OTf)2 allowed the isourea transformation
to be complete in 16 h at room temperature (Scheme 5).
5900 J . Org. Chem., Vol. 69, No. 18, 2004

Polymer-Supported O-Alkylisoureas
TABLE 2. Op tim iza tion of th e Ester ifica tion Rea ction
entry
T (°C)
time
equiv of 4a
conversion
1
2
3
4
5
6
reflux
rt
reflux
reflux
reflux
reflux
16 h
3 d
16 h
16 h
16 h
10 h
3
3
1.2
1.5
1.8
2
complete
incomplete
incomplete
incomplete
incomplete
complete
F IGURE 2. Effect of resin washing with TMEDA solutions
in CH2Cl2: (left) first washing; (right) third washing. The resin
is floating on top of the solvent.
times, which strongly indicated that immobilized tert-
butyl isourea instantly decomposes. This observation was
not expected, as it is possible to synthesize the corre-
sponding N,N′-diisopropyl-O-tert-butyl isourea in the
solution phase.
SCHEME 5. Syn th esis of P olym er -Su p p or ted
O-Alk ylisou r ea Ca ta lyzed by Cop p er (II) Tr ifla te
Alk yla tion of Ca r boxylic Acid s Usin g P olym er -
Su p p or ted O-Alk ylisou r ea s 4a -e. With a satisfactory
large-scale procedure for the different polymer-supported
O-alkylisoureas in hand, their reactivity toward carbox-
ylic acids was investigated. As a model reaction, the
conversion of 4-methylbenzoic acid 8 to the corresponding
methyl ester 9 was chosen (Table 2). When 8 was treated
with 3 equiv of 4a in refluxing THF, complete conversion
was achieved after overnight reaction. Importantly, a
simple filtration followed by two resin washes with
methanol and CH2Cl2 and finally evaporation of the
solvents afforded very pure product as judged by NMR
analysis. Further optimization was attempted with
respect to reaction time, temperature and amount of
resin. All experiments were conducted in THF as it
represented a good compromise between ability to swell
the resin, ability to solubilize carboxylic acid substrates
and ease of removal after reaction.
The studies showed that the best conditions comprise
refluxing in THF for 10 h with 2 equiv of resin. Never-
theless, to allow for slight differences of reactivity for
different acids, in all further experiments 2 equiv of resin
was used and the reactions were allowed to run for 16 h.
The full range of carboxylic acid substrates that were
used in our investigations is displayed in Figure 3, and
the results of the esterification reactions using the solid-
supported isoureas are shown in Table 3. All reactions
were worked-up as described above.
SCHEME 6. Syn th esis of P olym er -Su p p or ted
O-(Tr im eth ylsilyl)eth ylisou r ea Usin g Cop p er (I)
Ca ta lysis
Using these low levels of catalyst, the IR spectra of the
resin before washing with TMEDA revealed clear isourea
bands, together with the peaks attributed to the isourea-
copper complex. It appeared that TMEDA washings were
still required to completely remove all copper species.
This process was successfully applied for the preparation
of the O-benzyl, O-allyl, O-4-nitrobenzyl (PNB) isoureas
4b-d , as well as for O-methyl isourea 4a . No urea band
was visible for any of these isourea resins. Importantly,
the preparation of the resins could now be carried out
on large scale.
This procedure failed to form the corresponding 2-tri-
methylsilylethyl derivative 4e (Scheme 6), where strong
urea bands in the IR spectrum of the resulting resin were
1
observed. MAS H NMR and gel-phase 13C NMR analysis
evidenced almost complete absence of the TMS and of
the ethyl groups. A possible explanation involves an E1
elimination catalyzed by the Lewis acid, which would be
facilitated by the presence of the TMS group, forming
ethylene and polymer-bound N-trimethylsilylurea. The
resulting silicon-nitrogen bond could have been easily
hydrolyzed during the subsequent resin washes. In the
event, employing the milder Cu(I) triflate as catalyst gave
satisfactory results for the preparation of 4e.
Unfortunately, the solid-supported tert-butyl isourea
could not be obtained using this process. Under all
conditions tested, IR spectra displayed only urea bands
and/or carbodiimide bands, and an isourea band was
never observed when analyzed after various reaction
Simple carboxylic acids (entries 1-10) were alkylated
in good yields and excellent purities using the im-
mobilized isoureas 4a -d . However, long-chain aliphatic
acids (entries 9-10), while also yielding pure esters in
high yield, required much longer reaction times. Presum-
ably, this observation was due to increased hydrophobic
interactions with the polystyrene-based resin, slowing
down diffusion rates. In agreement with the correspond-
ing reactions with N,N′-diisopropyl-O-alkylisoureas in
homogeneous reaction media,15 the esterifications using
the polymer-supported version exhibited excellent chemo-
selectivity, even for the more reactive benzyl/allyl isoureas.
Hence, mandelic acid (entries 11 and 12) and Boc-
protected serine (entries 25-27) were cleanly alkylated
J . Org. Chem, Vol. 69, No. 18, 2004 5901

Crosignani et al.
F IGURE 3. Substrates for the esterification reaction experiments.
TABLE 3. O-Alk yla tion of Ca r boxylic Acid s Usin g
Resin s 4a -d
evident that isoureas were too basic for the Fmoc group
to survive. Amides were also untouched with Boc-
protected glutamine cleanly converted into the corre-
sponding esters (entries 22-24).
Very importantly, all products were obtained in very
good purity, as judged by 1H and 13C NMR after removal
of the resin by filtration and evaporation of the reaction/
wash solvents. A typical result is reproduced in Figure
4. The purity of the methyl esters was generally slightly
higher than that of the other esters, which was attributed
to the different preparation between the O-methyl isourea
resin (135 °C) and the other resins (at room temperature).
The high temperature presumably caused release of the
resin impurities at that stage, which were then removed
by washing the resin with CH2Cl2 to remove the traces
of methanol (see above).
A concern for the reactions with the benzylic isoureas
was that the isomerization to the corresponding urea as
observed during their thermal preparation (see Scheme
4) could interfere with the ester formation reactions at
the employed temperature. However, the excellent yields
that were observed prove that the ester formation is a
faster process.
For application in parallel synthesis, the methodology
employed ideally should lead to high compound purity,
regardless of the reactivity of the starting materials.
Though most of the compounds in Table 3 indeed were
obtained in high purity, the fatty acids proved to be slow
reacting. To overcome such inherent reactivity differ-
ences, should an automated setup be employed using a
set reaction time, a scavenging procedure18 for this
process using aminomethyl polystyrene was developed
(Scheme 7).
Treatment of oleic acid 13 with isourea resin 4a under
typical conditions (16 h) gave a mixture of 70% ester and
30% unreacted oleic acid. When, after reaction, 4.5 equiv
of basic scavenging resin was added, followed by a
filtration and solvent evaporation step, a product of >98%
purity was obtained.
yielda (%)
entry
acid
R
time (h)
ester
(purity (%))b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
10
10
10
10
11
11
11
11
12
13
14
14
15
15
15
15
16
17
17
17
17
18
18
18
19
19
19
Me
Bn
16
16
16
16
16
16
16
16
40
40
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
20a
20b
20c
20d
21a
21b
21c
21d
22a
23a
24a
24d
25a
25b
25c
25d
26a
27a
27b
27c
27d
28a
28b
28c
29b
29c
29d
81 (>98)
96 (>95)
82 (>95)
94 (>95)
94 (>98)
99 (>95)
85 (>95)
94 (>95)
91 (>98)
88 (>98)
90 (>98)
92 (>95)
78 (93)
96 (>95)
90 (>95)
99 (>95)
74 (>98)
81 (>98)
97 (>95)
93 (>95)
98 (>95)
82 (>98)
98 (>95)
94 (>95)
99 (>95)
98 (>95)
99 (>95)
All
PNBc
Me
Bn
All
PNBc
Me
Me
Me
PNBc
Me
Bn
All
PNBc
Me
Me
Bn
All
PNBc
Me
Bn
All
Bn
All
PNBc
Isolated yield. Determined by H NMR. c PNB ) p-nitroben-
a
b
1
zyl.
to give the corresponding ester with no detectable ether
formation. When phenolic groups were present (entries
13-16), a small amount of dialkylation was observed
when treated with O-methylisourea resin 4a (entry 13),
though the selectivity remained acceptable, and only
about 3.5% of dialkylated product was formed (1H NMR).
Perhaps surprisingly, reaction of 3-methylsalicyclic acid
15 with the more reactive benzyl and allyl isoureas did
not give the corresponding ether byproducts (entries 14-
16). Boc-protected amino acids (entries 17-24) could also
be cleanly transformed into the corresponding amino
esters using all the isourea reagents. In contrast, the
esterification was not successful with Fmoc-protected
amino acids. When Fmoc-glycine was employed, no corre-
sponding methyl ester could be observed. As dibenzo-
fulvene was isolated from the reaction mixture, it was
Unfortunately, the reactions using the 2-trimethyl-
silyl isourea resin 4e were not as successful. Even when
up to 4 equiv of the resin was used for 4 days at 60 °C,
low conversions (ca. 60%) were obtained. Most unsatis-
factorily, the purity was very low even after employing
the basic scavenging protocol described above. Surpris-
ingly, a reaction at room temperature led to a higher
conversion, but nevertheless gave a lower product purity.
(18) 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.
5902 J . Org. Chem., Vol. 69, No. 18, 2004

Polymer-Supported O-Alkylisoureas
F IGURE 4. 1H NMR spectrum of crude ester 20a .
SCHEME 7. Use of a Ba sic Sca ven ger To Rem ove Un r ea cted Acid for Libr a r y Gen er a tion
Considering the sensitivity of this resin toward elimina-
tion reactions (see above), it is perhaps not entirely
surprising that complete conversions of the carboxylic
acid into the TMS-ethyl ester could not be achieved, as
elimination of the polymer-supported isourea to give
ethylene would become increasingly competitive as the
acid concentration decreases toward the end of the
reaction.
Micr ow a ve-Assisted Ester ifica tion Rea ction s. Al-
though the high yields and purities that were obtained
should make the above-described methodology attractive
for general use, the drawback is the long reaction time
required for complete conversion. As we have demon-
strated that the reaction between carboxylic acids and
N,N′-diisopropyl-O-alkylisoureas is greatly accelerated
when employing much higher temperatures under micro-
wave irradiation,11b the use of this heating technique in
conjunction with the isourea based resins was investi-
gated.19 Following the experiments described in the
previous section, THF was initially used as solvent, for
which a maximum temperature of 120 °C could be
obtained in the microwave oven. However, more than 5
min was necessary to reach the maximum temperature
(a time which is included in the overall heating time).
Hence, it was decided to switch to acetonitrile which,
having a larger tan δ value, is more efficient in converting
microwave irradiation to heat19c and is also a good solvent
for carboxylic acids. A temperature of 130 °C could be
reached within 1 min. A comparison between the two
conditions was made for solid-supported O-methylisourea
reactions (Table 4). All reactions in THF were complete
in 15 min, except for 3-phenylpropionic acid (entry 3) and
for oleic acid (entry 5), which required 20 min reaction
time and a slightly higher excess of resin. In contrast,
reactions in acetonitrile were complete in merely 5 min,
with the sole exception of oleic acid (8 min). Under the
high-temperature conditions used, no significant degra-
(19) Reviews on microwave-assisted reactions: (a) Swamy, K. M.
K.; Yeh, W.; Lin, M.; Sun, C. Curr. Med. Chem. 2003, 10, 2403-2423.
(b) Blackwell, H. E. Org. Biol. Chem. 2003, 1, 1251-1255. (c) Lidstro¨m,
P.; Tierney, J .; Wathey, B.; Westman, J . Tetrahedron 2001, 57, 9225-
9283.
J . Org. Chem, Vol. 69, No. 18, 2004 5903

Crosignani et al.
TABLE 4. Syn th esis of Meth yl Ester s Usin g Resin 4a
u n d er Micr ow a ve Ir r a d ia tion
corresponding benzyl and PNB esters (entries 4 and 5)
in very high purity, with very low levels of dialkylation.
The results indicate that even at this temperature the
possible isomerization to the urea products, as observed
when using microwave irradiation (at similar tempera-
tures) for the synthesis of solid-supported O-benzyliso-
urea, is a slower process than the ester formation. In
contrast, the negative results obtained with O-(tri-
methylsilylethyl)isourea resin in THF at 60 °C overnight
were confirmed under microwave irradiation conditions.
Only traces of the esterification products could be de-
tected, signifying that in this case the elimination reac-
tion is more favorable at these high temperatures.
time
(min)
yielda (%)
entry
acid
solvent
ester
(purity (%))b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
10
10
11
11
13
13
14
14
15
15
16
17
17
18
THF
CH3CN
THF
CH3CN
THF
CH3CN
THF
CH3CN
THF
CH3CN
THF
THF
CH3CN
THF
15
5
20
5
20
5
15
5
15
5
15
15
5
20a
20a
21a
21a
23a
23a
24a
24a
25a
25a
26a
27a
27a
28a
86 (>98)
90 (>98)
79 (98)
83 (>98)
85 (>98)
96 (>98)
84 (>98)
76 (>98)
75 (98)
Con clu sion s
We have demonstrated that it is possible to prepare a
range of polymer-supported O-alkylisoureas in an easy,
scalable manner from commercially available resins. Of
the examples investigated, the only exception was the
tert-butyl derivative, which proved to be too unstable and
was never isolated. Polymer-supported O-methyl, O-
benzyl, O-allyl, and O-p-nitrobenzyl isourea reagents
efficiently convert carboxylic acids into esters in high
yields and with excellent purities and chemoselectivities.
Apart from resin filtration and solvent evaporation no
further workup/purification is necessary. A scavenger
protocol has also been developed to ensure that only
products with high purities are obtained when less
reactive substrates are employed. The potential of micro-
wave-assisted chemistry for the use of the polymer-
supported isoureas has also been demonstrated, leading
to drastically reduced reaction times. The combination
of the short reaction times achievable under microwave
irradiation with the extremely simple workup procedure
granted by the polymer-supported reagents is particu-
larly advantageous, with the total time required to obtain
the final product amounting to less than 1 h. Hence, the
reported method should be attractive for both synthetic
organic as well as for combinatorial synthesis applica-
tions.
78 (89)
82 (>98)
92 (>98)
94 (>98)
75 (>98)
15
a
b
Isolated yield. Determined by 1H NMR.
TABLE 5. Syn th esis of Ester s Usin g Resin s 4a -d u n d er
Micr ow a ve Ir r a d ia tion in Aceton itr ile
time
(min)
yielda
(%)
entry
acid
R
T (°C)
ester
1
2
3
4
5
6
7
8
9
10
10
14
15
15
17
17
18
19
19
Bn
125
130
130
125
130
125
125
125
125
130
3
5
5
3
5
3
3
3
3
5
20b
20d
24d
25b
25d
27b
27c
28c
29c
29d
96
89
98
93
97
89
93
91
94
88
PNB
PNB
Bn
PNB
Bn
All
All
All
PNB
10
a
Isolated yields. All products had >95% purity (NMR).
Exp er im en ta l Section
Syn th esis of N-Cycloh exyl-N′-m eth ylp olystyr en e Ur ea
6. Aminomethyl polystyrene (5.00 g, 16 mmol) was swollen in
anhydrous THF (40 mL) in a round-bottomed flask. Cyclohexyl
isocyanate (10 mL, 80 mmol) was added in one portion under
stirring. Gentle stirring was continued overnight, and then
the reaction mixture was heated at reflux for 6 h. The resin
was collected by filtration, washed with CH2Cl2, DMF, MeOH,
and CH2Cl2, and dried overnight in a vacuum oven at 40 °C
to give the title compound (6.85 g).
dation of the resin was observed. The chemoselectivity
remained as excellent as in the experiments using
conventional heating, and all products exhibited very
high purities as evidenced from the NMR spectra (see
the Supporting Information). The only instance in which
the use of acetonitrile instead of THF proved to be
detrimental to the purity of the product was when an
acid bearing a phenolic group was employed (entries 9
vs 10): in this case, a higher level of dialkylation was
observed in the reaction for which acetonitrile was used
as solvent.
Nevertheless, acetonitrile was clearly a superior sol-
vent than THF, and hence, it was used subsequently for
the investigations using the other immobilized isoureas
(Table 5). For the more reactive O-benzyl and O-allyl
isoureas, all reactions were complete in just 3 min, while
for the p-nitrobenzylisourea derivative 5 min at 130 °C
were required. In contrast with the O-methylisourea
resin, the reaction of 3-methylsalicylic acid led to the
IR (neat): νmax/(cm-1) 1627 (s), 1552 (s). 13C NMR (75.47
MHz; CDCl3) δC: 158.0; 48.8; 40.4; 33.8; 24.9.
Syn th esis of N-Cycloh exyl-N′-m eth ylp olystyr en e Ca r -
bod iim id e 3. N-Cyclohexyl-N′-methylpolystyrene urea 6 (2.00
g, 4.6 mmol) was swollen in CH2Cl2 (30 mL), and triphenyl-
phosphine (3.46 g, 13.2 mmol) was added. The mixture was
stirred for 10 min to allow complete dissolution of the tri-
phenylphosphine, upon which CBr4 (4.40 g, 13.2 mmol) was
added, immediately followed by dropwise addition of Et3N (6.0
mL, 43 mmol). The dark reaction mixture was gently stirred
overnight, and then the resin was collected by filtration,
washed with CH2Cl2, DMF, and CH2Cl2, and dried overnight
in a vacuum-oven at 40 °C to give the title compound (1.82 g).
5904 J . Org. Chem., Vol. 69, No. 18, 2004

Polymer-Supported O-Alkylisoureas
IR (neat): νmax/(cm-1) 2117 (s). 13C NMR (75.47 MHz; CDCl3)
δC: 145.1; 55.6; 50.5; 34.8; 25.5; 24.5.
resin (0.35 mmol) in a round-bottom flask. The mixture was
heated at 60 °C under gentle stirring for the time indicated,
and then the resin was removed by filtration and washed with
MeOH and CH2Cl2. The combined filtrates were evaporated
to afford the desired carboxylic ester. No purification was
performed before NMR analysis.
Syn th esis of O-Meth yl-N-cycloh exyl-N′-m eth ylp oly-
styr en e Isou r ea 4a u n d er Micr ow a ve Ir r a d ia tion . N-
Cyclohexyl-N′-methylpolystyrenecarbodiimide 3 (500 mg, 0.900
mmol) was placed in a microwave vial. The vial was capped,
and anhydrous methanol (3 mL) was added under nitrogen
via a syringe. The vial was then heated under microwave
irradiation at 135 °C for 70 min (internal pressure 9 bar). The
resin was then collected by filtration, washed with CH2Cl2,
and dried overnight in a vacuum oven at 40 °C to give the
title compound (490 mg).
Syn th esis of Meth yl Olea te 23 Usin g th e Sca ven ger
P r otocol. Oleic acid 13 (44.5 mg, 0.175 mmol) was dissolved
in THF (2 mL), and the resulting solution was added to the
isourea-resin (200 mg, 0.35 mmol) in a round-bottom flask.
The mixture was heated overnight at 60 °C under gentle
stirring. Aminomethylpolystyrene (loading 0.8 mmol/g) was
added in portions until TLC analysis showed complete dis-
appearance of the oleic acid, for a total of 100 mg of resin
added. The resins were removed by filtration and washed with
MeOH and CH2Cl2. The combined filtrates were evaporated
to afford methyl oleate 23 as a colorless oil (24.9 mg, 53%).
Gen er a l Meth od for th e Micr ow a ve-Assisted Syn th e-
sis of Meth yl Ester s Usin g Solid -Su p p or ted Isou r ea s. The
carboxylic acid (0.175 mmol) was dissolved in THF or CH3CN
(2 mL), and the resulting solution was added to the resin (0.35
mmol) in a microwave vial. The vial was capped and heated
under microwave irradiation for the time and at the temper-
ature indicated, and then the resin was removed by filtration
and washed with MeOH and CH2Cl2. The combined filtrates
were evaporated to afford the desired carboxylic ester. No
purification was performed before NMR analysis.
4a : IR(neat): νmax/(cm-1) 1655 (s); 1329 (s). 13C NMR (75.47
MHz; CDCl3) δC: 154.3; 53.0; 50.1; 34.2; 25.4; 24.8.
Gen er a l P r oced u r e for th e Syn th esis of O-Alk yl-N-
cycloh exyl-N′-m eth ylp olystyr en e Isou r ea s 4a -d u n d er
Cu (OTf)2 Ca ta lysis. Polymer-supported carbodiimide 3 (2.00
g, 3.60 mmol) and Cu(OTf)2 (50 mg, 0.14 mmol) were sus-
pended in a mixture of anhydrous THF (6 mL) and the
appropriate alcohol (15-99 mmol). The mixture was gently
stirred at room temperature for 16 h, and then the resin was
collected by filtration and washed with a 10% solution of
TMEDA in CH2Cl2 until the washing solution remained
colorless and then with DMF, MeOH, and CH2Cl2. The resin
was dried at 40 °C under vacuum for 24 h to afford the title
compound.
4b: IR(neat): νmax/(cm-1) 1656 (s), 1321 (s). 13C NMR (75.47
MHz; CDCl3) δC: 67.0; 55.6; 50.3; 34.8; 25.5; 24.5.
4c: IR (neat): νmax/(cm-1) 1656 (s), 1316 (s). 13C NMR (75.47
MHz; CDCl3) δC: 133.7; 115.9; 65.7; 55.4; 49.9; 34.5; 34.0; 25.2;
24.3.
Ack n ow led gm en t. We acknowledge the supporting
partners of the Southampton Combinatorial Centre of
Excellence for financial support. The funding partners
are Amersham Health and Amersham Biosciences,
AstraZeneca, Evotec OAI Ltd., GlaxoSmithKline, Eli
Lilly, Merck Biosciences Inc., Organon, Pfizer, and
Roche. We thank J oan Street and Neil Wells for as-
sistance with NMR, NovaBiochem for supplying resin
5, and Personal Chemistry for the donation of a Smith
Synthesizer. We wish to acknowledge the use of the
EPSRC’s Chemical Database Service at Daresbury.20
4d : IR (neat): νmax/(cm-1) 1664 (s), 1340 (s), 1319 (s). 13C
NMR (75.47 MHz; CDCl3) δC: 145.6; 123.2; 65.2; 50.1; 34.0;
24.5.
Syn th esis of O-(2-Tr im eth ylsilyleth yl)-N-cycloh exyl-
N′-m eth ylp olystyr en e Isou r ea 4e. Polymer-supported car-
bodiimide 3 (1.00 g, 1.80 mmol), 2-trimethylsilylethanol (2.00
mL, 14 mmol), and copper(I) triflate-toluene complex (2:1) (20
mg, 0.077 mmol) were suspended in DMF (10 mL). Stirring
was continued overnight, and then the resin was collected by
filtration, washed with a solution of TMEDA (10% in CH2Cl2),
DMF, MeOH, and CH2Cl2, and dried for 40 h in a vacuum
oven, giving the title compound (1.12 g).
1
Su p p or tin g In for m a tion Ava ila ble: IR, MAS H NMR,
and gel-phase 13C NMR spectra of all resins. 1H and 13C NMR
spectra of all esters. This material is available free of charge
via the Internet at http://pubs.acs.org.
IR (neat): νmax/(cm-1) 1654 (s), 1319 (s), 1245 (s), 832 (s).
13C NMR (75.47 MHz; CDCl3) δC: 63.2; 49.6; 33.8; 24.5; 17.2;
-1.6.
Gen er a l P r oced u r e for Ester ifica tion s Usin g Solid -
Su p p or ted O-Alk ylisou r ea s w ith Con ven tion a l Hea tin g.
The carboxylic acid 10-19 (0.175 mmol) was dissolved in THF
(2 mL), and the resulting solution was added to the isourea-
J O049239E
(20) The United Kingdom Database Service. Fletcher, D. A.; Mc-
Meeking, R. F.; Parkin, D. J . Chem. Inf. Comput. Sci. 1996, 36, 746-
749.
J . Org. Chem, Vol. 69, No. 18, 2004 5905