as 1, but it has the advantage of being readily removed, along
with the corresponding urea byproduct, with a simple acidic
workup.
Table 2. Synthesis of Carboxylic Esters with Resin 3
However, in our hands reproducible or satisfactory results
could not be obtained when isourea 2 was used for
microwave-assisted ester formation reactions. We attributed
the problem to our inability to obtain pure samples of 2.
Hence it was decided to modify the synthesis of this reagent
(Scheme 2): isourea 2 was prepared by microwave irradia-
time
yielda
(%)
purityb
(%)
entry
acid
(min)
1
2
3
4
5
6
7
8c
4a
4b
4c
4d
4e
4f
15
20
15
15
15
15
15
20
86
79
84
75
82
92
75
85
>98
98
>98
98
>98
>98
>98
>98
Scheme 2. Esterification Reactions with O-Alkylisourea 2
4g
4h
1
a Isolated yield. b Determined by H NMR. c 2.5 equiv of 2 were used.
required a slightly longer reaction time, and 4h, which
required the use of 2.5 equiv of resin for 20 min. Under the
conditions used, we have not observed any significant
degradation of the resin. All the functional groups that were
unreactive toward the reagent with conventional heating were
not touched either in the microwave-accelerated reactions.
The most important feature of this reagent is, however,
the simplicity of the workup: simple filtration of the resin,
followed by evaporation of the solvent afforded the desired
products, in all cases with purities of at least 98% (deter-
tion of a solution of the corresponding carbodiimide, which
is commercially available, in dry methanol. After removal
of the solvent under vacuum, the crude product was
immediately used to perform the alkylation. This approach
avoids the use of a copper catalyst, which considerably
facilitates the isolation of 2. With use of isourea 2 prepared
via this procedure, esterification, which was complete within
5 min, followed by an acidic aqueous workup as described
by Rapoport yielded pure compound 5a in good yield
(Scheme 2).
Nevertheless, while the required acidic workup is compat-
ible with standard peptide synthesis, it does restrict the scope
with respect to substrate substitution for the esterification
reaction. In addition, 5 equiv of reagent are needed to drive
the reaction to completion.
The use of solid-supported O-methylisourea allows for a
simple purification protocol, leading to pure methyl esters.13
However, overnight reflux in THF is required for complete
reactions. Hence, microwave irradiation of reactions with this
solid-supported reagent would be an important test case. In
the event, with 2 equiv of resin, most esterifications were
completed in 15 min.14 The exceptions were 4b, which
1
mined by H and 13C NMR). No further purifications were
performed on any of the products obtained.
The combination of microwave technology, which con-
siderably cuts down reaction times, and polymer-supported
reagents, which simplifies workup procedures, enables the
synthetic chemist to obtain the pure methyl esters in less
than an hour.
In conclusion, we have studied the effect of microwave
irradiation on the reaction of carboxylic acids with three
different O-alkylisoureas. All reactions are complete within
5 min for homogeneous reactions and within a maximum of
20 min when the solid-supported reagent was used. In all
cases the chemoselectivity of the reaction is excellent. The
use of a polymer-bound reagent enabled us to maximize the
timesaving effect of microwave technology.
Acknowledgment. The authors thank Personal Chemistry
for the donation of a Smith Synthesizer. The authors
acknowledge the supporting partners of the Southampton
Combinatorial Centre of Excellence for financial support.
The funding partners are Amersham Health and Amersham
Biosciences, AstraZeneca, GlaxoSmithKline, Eli Lilly, CN
Biosciences, Inc., Organon, Pfizer, and Roche. The authors
thank Joan Street and Neil Wells for assistance with NMR.
(11) Sheehan, J. C.; Cruickshank, P. A.; Boshart G. I. J. Org. Chem.
1961, 26, 2525-2528.
(12) Gibson, F. S.; Park, M. S.; Rapoport, H. J. Org. Chem. 1994, 59,
7503-7507.
Supporting Information Available: Experimental pro-
cedures for microwave assisted esterifications with isoureas
1-3 and 1H and 13C NMR spectra of compounds 5
synthesized with isourea 3. This material is available free
(13) Crosignani, S.; White, P. D.; Linclau, B. Org. Lett. 2002, 4, 1035-
1037.
(14) A typical procedure is as follows: the carboxylic acid 4 (0.175
mmol) is dissolved in 2 mL of THF. The solution is added to resin 2 (200
mg, 0.35 mmol) in a microwave vial. The vial is heated at 120 °C for 15
min in a Smith Synthesizer, followed by filtration of the resin with
subsequent resin wash (MeOH, 3 × 2 mL and DCM, 3 × 3 mL). The
solvent is then evaporated under reduced pressure to give the desired product.
OL0263705
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