Polymer-supported O-benzyl and O-allylisoureas: Convenient preparation and use in ester synthesis from carboxylic acids

Article abstract of DOI:10.1021/ol0275062

Polymer-supported O-methyl, O-benzyl, and O-allyl-isoureas were prepared by copper(II)-catalyzed reaction of polymer-supported carbodiimide with the corresponding alcohols. These polymer-supported reagents were successfully employed to convert a series of carboxylic acids to methyl, benzyl, or allyl esters, in good yields. The products were obtained with high purity (>95% by NMR) after a simple resin filtration-solvent evaporation sequence.

Full text of DOI:10.1021/ol0275062

ORGANIC
LETTERS
2003
Vol. 5, No. 6
853-856
Polymer-Supported O-Benzyl and
O-Allylisoureas: Convenient Preparation
and Use in Ester Synthesis from
Carboxylic Acids
,†
Stefano Crosignani,† Peter D. White,‡ Rene Steinauer,§ and Bruno Linclau*
Combinatorial Centre of Excellence, Chemistry Department, UniVersity of
Southampton, Southampton, SO17 1BJ, United Kingdom, NoVabiochem,
Merck Biosciences Ltd., Padge Road, Beeston, NG9 2JR, United Kingdom, and
Merck Biosciences AG, Weidenmattweg 4, CH-4448 La¨ufelfingen, Switzerland
bruno.linclau@soton.ac.uk
Received December 19, 2002
ABSTRACT
Polymer-supported O-methyl, O-benzyl, and O-allyl-isoureas were prepared by copper(II)-catalyzed reaction of polymer-supported carbodiimide
with the corresponding alcohols. These polymer-supported reagents were successfully employed to convert a series of carboxylic acids to
methyl, benzyl, or allyl esters, in good yields. The products were obtained with high purity (>95% by NMR) after a simple resin filtration−
solvent evaporation sequence.
In the past decade, the availability of automated screening
techniques has put a major emphasis on the number of
compounds that can be produced per unit of time.
In this respect, the use of polymer-supported reagents has
proven to be extremely useful, not least due to the successful
combination of the advantages of both solution-phase and
solid-phase chemistry. Many solid-supported reagents allow
for a single filtration/evaporation sequence in order to isolate
the desired product in good yield and purity.1 The develop-
ment of new immobilized reagents for which this simple
workup protocol is sufficient is currently an important
research area. Whereas the use of solid-supported reagents
so far is mainly employed in parallel synthesis, recent reports
convincingly proved their usefulness in traditional total
synthesis applications.2 Although a great variety of im-
mobilized reagents have now been described, allowing for
increasingly complex reaction processes to be accomplished,
some basic transformations were overlooked for a long time.
It took until 2001 before two groups independently described
triazene-based resins as the first “alkylating resins” to achieve
the conversion of carboxylic acids into the corresponding
esters.3 Reacting commercial solid-supported diazonium with
† University of Southampton.
‡ Merck Biosciences Ltd.
§ Merck Biosciences AG.
(2) (a) Baxendale, I. R.; Ley, S. V.; Piutti C. Angew. Chem., Int. Ed.
2002, 41, 2194-2197. (b) Baxendale, I. R.; Lee, A. L.; Ley, S. V. Synlett
2001, 1482-1484.
(3) (a) Pilot, C.; Dahmen, S.; Lauterwasser, F.; Bra¨se S. Tetrahedron
Lett. 2001, 42, 9179-81. (b) Rademann, J.; Smerdka, J.; Jung, G.; Grosche,
P.; Schmid, D. Angew. Chem., Int. Ed. 2001, 40, 381-385.
(1) (a) 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, 3815-4195. (b) Shuttleworth,
S. J.; Allin, S. M.; Wilson, R. D.; Nasturica, D. Synthesis 2000, 1035-
1074.
10.1021/ol0275062 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/25/2003

primary alkylamines at low temperatures formed immobilized
triazenes, which were able to convert carboxylic acids into
carboxylic esters. Subsequently, we have described that solid-
supported O-methylisourea, readily synthesized from com-
mercial carbodiimide resin and methanol, is an excellent
reagent for the formation of methyl esters from carboxylic
acids, with reaction times as short as 15 min when executed
under microwave irradiation.4
In this communication, we report our results regarding the
O-benzylation and O-allylation of carboxylic acids using the
corresponding solid-supported isoureas under both thermal
and microwave-assisted reaction conditions. In addition, we
disclose an improved, more practical synthesis of solid-
supported isoureas.
We have reported the preparation of solid-supported
O-methylisourea by heating polymer-supported carbodiimide
1 under microwave irradiation in methanol as a solvent. No
other reagents were used, obviating the need for any sub-
sequent resin washing operations. Following this successful
preparation, we attempted to synthesize O-benzyl and O-allyl
isoureas in a similar way.
Although the urea byproduct would not interfere in the
ester formation reaction, the result is a decrease in isourea
loading, and an alternative preparation was desirable. In
addition, the procedure using microwave irradiation is only
possible on a small scale (0.5 g), and a modified preparation
suitable for larger scale production of isourea resins was
required.
The formation of isoureas is known to be easily ac-
complished by reaction of a carbodiimide and an alcohol
under CuCl catalysis,7 a process that is possible at room
temperature. As we reasoned that the rearrangement was
accelerated at high temperature, a low-temperature process
could prove to be successful.
We selected copper(II) triflate as the catalyst, not only
because of its greater solubility in THF and easy handling
and stability but also because, in our experience, it is superior
to CuCl in its activity for isourea formation. Hence, carbo-
diimide resin 1 was treated with benzyl alcohol (9 equiv) in
THF and a catalytic amount (7 mol %) of Cu(OTf)2 (Scheme
2). Gratifyingly, we observed no detectable trace of urea
Hence, solid-supported carbodiimide resin 1 (Scheme 1)5
was suspended in benzyl alcohol and heated under micro-
Scheme 2. Copper-Catalyzed Synthesis of O-Alkylisoureas
Scheme 1. Microwave-Assisted Synthesis of O-Benzylisourea
formation by IR, while the carbodiimide band completely
disappeared.8 Identical results were obtained using allyl
alcohol as a reagent.
To remove the copper species after reaction, the resin was
subjected to solvent washings. Unfortunately, we were not
able to fully eliminate the copper species by repeated wash
cycles with a variety of solvents. The failure to remove the
catalyst represented a concern because ester formation using
isourea resins that still were contaminated with copper salts
did not proceed to completion. However, a mixture (10%
v/v) of N,N′-tetramethylethylenediamine (TMEDA) in di-
chloromethane (DCM) as a washing solvent resulted in
complete removal of the copper catalyst, through diamine
complexation to the copper species. As the copper-diamine
complex has an intense deep blue color, visual monitoring
of the washing operation is very straightforward. It is worth
noting that monoamine species were not able to effect
complete removal of the copper catalyst. While amine
hydrochloride salts and amino acids are known to react with
isoureas to form quaternary ammonium salts,9 neutral amines
do not react with isoureas. We have observed no degradation
wave irradiation until disappearance of the strong carbo-
diimide IR absorption band (2119 cm-1). However, from the
IR spectra, it was apparent that apart from the expected
isourea absorption bands (1654 and 1329 cm-1), another
strong absorption was present, indicating a urea group (1640
and 1555 cm-1). When O-methylisourea was prepared in this
way, no urea band was observed. The formation of the urea
bands could be explained by a rearrangement of 2a to the
corresponding immobilized N-benzyl urea 3. Resubjecting
this resin to the same conditions led to an increase in the
proportion of urea compared to the isourea bands. Although
we have no direct proof of the exact structure of the urea
byproduct, there is solution-phase precedent for similar
rearrangements of isoureas to the corresponding N-substituted
urea products.6
(4) (a) Crosignani, S.; White P. D.; Linclau, B. Org. Lett. 2002, 6, 1035-
1037. (b) Crosignani, S.; White P. D.; Linclau, B. Org. Lett. 2002, 6, 2961-
2963.
(5) We have used both commercial carbodiimide resin (loading 1.8 mmol/
g) and resin prepared “in-house” from aminomethyl polystyrene resin
(loading 3.2 mmol/g) in two steps: reaction with cyclohexylisocyanate in
THF (Weinshenker, N. M.; Shen, C. M.; Wong, J. Y. Org. Synth. 1977,
56, 95-99), followed by dehydration (PPh3, CBr4, TEA, DCM, 16 h; Lange,
U. E. W. Tetrahedron Lett. 2002, 43, 6857-6860).
(7) Mathias, L. J. Synthesis 1979, 561-576.
(8) Use of the copper catalyst (7 mol %) under microwave irradiation
accelerates the formation of both the desired isourea 2a and the urea
byproduct: after 5 min at 100 °C, the IR spectrum shows a complete
disappearance of the carbodiimide absorption band, while both isourea and
urea bands are present. After 30 min at 120 °C, only the urea bands are
visible.
(6) Tsuboi, S.; Stromguist, P.; Overman, L. E. Tetrahedron Lett. 1976,
17, 1144-1148.
(9) Musich J. A.; Rapoport H. J. Org. Chem. 1977, 42, 139-141.
854
Org. Lett., Vol. 5, No. 6, 2003

of 2 after prolonged treatment with the diamine solution,
even in the presence of Cu(OTf)2.
and 9) were unreactive under the reaction conditions even
by the more reactive benzyl isourea. Boc-protected amines
(entries 4-6 and 10-12) proved to be stable under these
conditions. Finally, primary amides were also not touched
(entries 5 and 11).
No other reagent is needed for the reaction, and as both
the urea byproduct and any excess isourea remain im-
mobilized on the polystyrene beads, a simple filtration of
the resin followed by two washings with DCM and evapora-
tion of the solvent affords the product: all the isolated yields
are good to excellent, and all the products were obtained in
excellent purity.10
We also performed some esterification reactions with the
solid-supported O-methylisourea 2c, prepared via the Cu(II)-
catalyzed procedure (entries 13-14), and the results show
that the method of reagent preparation does not play a
significant role with regard to yield and purity of the methyl
ester products.
The use of microwave irradiation is becoming a common
technique for obtaining increased rates of reactions on the
solid phase, which otherwise suffer from slower kinetics.11
In a previous communication,4b we demonstrated that the
time needed for the esterification of carboxylic acids using
O-alkylisoureas can be significantly reduced by performing
the reaction under microwave irradiation. When using
polymer-supported reagent 2c, most reactions were complete
in just 15 min at a temperature of 125 °C, using THF as a
solvent. However, due to its low polarity, THF does not
absorb microwave irradiation efficiently. When reactions are
performed on rather dilute solutions, as is the case when
polymer-supported reagents are employed, this results in a
relatively slow increase in the reaction temperature and also
limits the maximum temperature achievable.12 To further
reduce the reaction time of our esterification reactions, we
decided to use acetonitrile as a solvent. Due to its higher
polarity, higher reaction temperatures can be achieved in a
shorter time under microwave irradiation. The results of the
microwave-assisted experiments are listed in Table 2.
The formation of solid-supported O-methylisourea was
also possible using this methodology. The copper-catalyzed
isourea formation is superior compared to the thermal
method, not only because of the absence of rearranged urea
products but also because upscaling is easier, as the
microwave oven is no longer required. Another benefit is
that the alcohol substrate is used not as the reaction solvent
but as a solution in THF, which considerably extends the
scope in terms of possible alcohol starting materials. Cur-
rently, 9 equiv of benzyl or allyl alcohol is used. Unfortu-
nately, all attempts to prepare polymer-supported O-tert-
butylisourea using tert-butyl alcohol as a reagent have failed
so far. From IR analysis, it appeared that no isourea bands
were visible at all, with only the carbodiimide and urea bands
being observed at any point during the reaction.
With an efficient preparation method of the O-benzyl and
O-allylisoureas in hand, we next turned to the formation of
benzyl and allyl esters from the corresponding carboxylic
acids.
Esterification of a series of carboxylic acids (Table 1) using
2a,b went smoothly using 2 equiv of reagent (based on the
Table 1. Synthesis of Carboxylic Esters Using 2a-c
Table 2. Microwave-Assisted Synthesis of Carboxylic Esters
Using 2a-c in Acetonitrile as a Solvent
entry acid
R
yielda purityb entry acid
R
yielda purityb
1
2
3
4
5
6
7
4a Bn 96% >95%
4b Bn 99% >95%
4d Bn 96% >95%
4e Bn 97% >95%
4f Bn 98% >95%
4g Bn 99% >95%
4a All 82% >95%
8
9
4b All 85% >95%
4d All 90% >95%
4e All 93% >95%
4f All 94% >95%
4g All 98% >95%
4a Me 83% >95%
4c Me 85% >95%
10
11
12
13
14
entry acid
R
temp (°C) time (min) yielda purityb
1
2
3
4
5
6
7
8
4a
4d
4e
4e
4f
4g
4a
4e
Bn
Bn
Bn
All
All
All
Me
Me
125
125
125
125
125
125
130
130
3
3
3
3
3
3
5
5
96%
93%
89%
93%
91%
94%
90%
94%
>95%
>95%
>95%
>95%
>95%
>95%
>95%
>95%
1
a Isolated yield. b Determined by H and 13C NMR.
resin loading, calculated assuming 100% conversion in each
preparation step). As we had observed previously for
polymer-supported O-methylisourea 2c,4 the chemoselectivity
of these isourea reagents is excellent, which demonstrates
their utility for the protection of polyfunctional molecules.
Both alcohols (entries 6, 12, and 14) and phenols (entries 3
a Isolated yield. b Determined by H and 13C NMR.
1
Org. Lett., Vol. 5, No. 6, 2003
855

Using the more reactive immobilized O-benzyl and O-allyl
isoureas led to the completion of all reactions in 3 min. While
we cannot exclude that rearrangement to the corresponding
N-benzyl or N-allyl urea products as shown in Scheme 1 is
not occurring at the high reaction temperature, the excellent
isolated yields suggest that the ester formation is a faster
process. With solid-supported O-methylisourea, the reaction
required 5 min at a slightly higher temperature, compared
to 15 min when THF is used as the reaction solvent. No
loss in chemoselectivity is observed compared to the standard
thermal heating. As reactions using solid-supported substrates
or reagents are known for requiring longer reaction times,
these results clearly illustrate the usefulness of microwave
irradiation for reactions on the solid phase and demonstrate
that very short reaction times are feasible. The combination
of these short reaction times with the extremely simple
workup procedure is particularly advantageous, with the total
time required to obtain the final product being less than 1 h.
In conclusion, a simple, inexpensive, and easy to scale-
up preparation of polymer-supported O-alkylisoureas has
been described. Using this method, we have prepared three
polymer-supported reagents capable of converting function-
alized carboxylic acids to the corresponding esters. The
groups that can be introduced are among the most used
protecting groups for carboxylic acids. The esterification
reactions can be performed either with conventional heating
or under microwave irradiation. In both cases, several
functional groups can be present in the substrate without
affecting the reaction. Most importantly, all products are
obtained in high purity after a simple resin filtration/solvent
evaporation protocol.
Acknowledgment. The authors acknowledge the sup-
porting partners of the Southampton Combinatorial Centre
of Excellence for financial support. The funding partners are
Amersham Health and Amersham Biosciences, AstraZeneca,
GlaxoSmithKline, Eli Lilly, Merck Biosciences Ltd., Or-
ganon, Pfizer, and Roche. The authors thank Joan Street and
Neil Wells for assistance with NMR and Personal Chemistry
for the donation of a Smith Synthesizer.
(10) When commercial carbodiimide 1 was used as a starting material,
the products obtained after the esterification reactions were contaminated
by unknown products. The authors believe that the harsh conditions
employed in the commercial preparation of 1 are responsible for this, and
that the use of a mild dehydration step to obtain carbodiimide 1 is essential
for obtaining polymer-supported isoureas that do not suffer from leaching.
(11) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R. J. Comb.
Chem. 2002, 4, 95-105.
Supporting Information Available: IR spectra and
experimental procedures for the preparation of resins 2a-c
1
and 1 and H and 13C NMR spectra of compounds 5a-g.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) In our experience, using 0.175 mmol of carboxylic acid and 2 mL
of THF, the maximum temperature achievable is around 130 °C.
OL0275062
856
Org. Lett., Vol. 5, No. 6, 2003