method suitable for automated solution-phase parallel syn-
thesis purposes.
O-Alkylisoureas are usually prepared through the reaction
2
of a carbodiimide and an alcohol under copper(I) catalysis.
However, preliminary experiments to prepare resin 2 using
this strategy were not satisfactory. As it was suggested in
the older literature that the transformation could be performed
5
at high temperatures without added catalyst, we decided to
investigate the thermal synthesis of the solid-supported
isourea 2. It is known that reactions at high temperatures
6
can be efficiently carried out under microwave irradiation.
Indeed, we found that irradiation of commercially available
7
carbodiimide resin 1 in dry methanol in a focused micro-
wave oven for 70 min resulted in complete conversion to
8
the O-methylisourea 2 (Scheme 1). Completion of the
reaction can be easily detected using IR, by monitoring the
-1
disappearance of the strong carbodiimide band at 2119 cm
and the development of two characteristic bands at 1654 and
-
1
1
329 cm .
This clean transformation does not require any catalyst or
reagent other than methanol, and the workup simply consists
of removing the methanol through filtration followed by
oven-drying to afford the desired O-methylisourea resin. It
is worth noting that although methanol is a poor solvent for
swelling polystyrene based resins, at these high temperatures
(
135 °C) the increased resin swelling allows reaction at all
9
available sites.
We subsequently investigated the usefulness of resin 2 as
a methylating agent for carboxylic acids. Preliminary experi-
ments showed that 2 equiv of resin 2 is sufficient to drive
the ester formation reaction to completion in a reasonable
time. Reactions at room temperature proceeded very slug-
gishly and did not reach completion even after 3 days.
a
Isolated yield. b Determined by H NMR. c 3.5% of 3f and 3.5% of
1
dimethylated product could be detected.
10
Reactions at 60 °C, however, were complete overnight. We
have monitored the reactions by TLC or HPLC. The results
are summarized in Table 1.
(
5) Dains, F. B. J. Am. Chem. Soc. 1899, 21, 136-192.
Simple carboxylic acids (entries 1-4) are alkylated in good
yields and excellent purities. The reaction requires longer
times with long-chain aliphatic acids (compare entries 3-4
with entry 2). Hydroxy acids (entry 5) are also cleanly
alkylated to give the corresponding hydroxy ester. No
alkylation of the alcohol moiety has been detected. When
phenolic groups are present (entry 6), a small amount of
dialkylation is observed. However, the selectivity remains
very good, and only about 3.5% of dialkylated product is
formed. Boc-protected amino acids (entries 7 to 9) can also
be cleanly transformed in the corresponding amino esters.
In contrast, we found that Fmoc groups are cleaved under
the reaction conditions. Amides are untouched as exemplified
(6) (a) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2
2
001, 57, 9225-9283. (b) Stadler, A.; Kappe, C. O. Eur. J. Org. Chem.
001, 919-925.
(7) N-Cyclohexylcarbodiimide-N′-methylpolystyrene HL 1 was provided
by Novabiochem (loading 1.80 mmol/g). Alternatively, it can be prepared
using the method described in Weinshenker, N. M.; Shen, C. M.; Wong, J.
Y. Org. Synth. 1977, 56, 95-99.
(8) The reaction is performed in a Smith Synthesizer, at a temperature
of 135 °C and a pressure of 9 bar.
9) The phenomenon has been attributed to a decreased solvent polarity
at higher temperatures: Westman, J. Org. Lett. 2001, 3, 3745-3747.
10) Typical experimental procedure: carboxylic acid 3 (0.175 mmol)
is dissolved in 2 mL of THF. The solution is added to resin 2 (200 mg,
.35 mmol). The mixture is heated at 60 °C with gentle stirring overnight;
then the resin is filtered and washed with MeOH (3 × 2 mL) and DCM (3
3 mL). The solvent is then evaporated under reduced pressure to give
the desired product.
(
(
0
×
1036
Org. Lett., Vol. 4, No. 6, 2002
Crosignani, Stefano
