Chighine et al.
SCHEME 1. Isourea-Mediated Ester Formation Starting
from O-Alkylisoureas 1 or via in Situ Formation of
O-Alkylisoureas Starting from Alcohols 5
equimolar addition of an alcohol 5 to a carbodiimide (e.g.,
diisopropylcarbodiimide DIC 6) under Cu(I) or Cu(II) cataly-
sis,12 with isolation achieved by filtration over Celite to remove
copper salts. Alternatively, isoureas can be synthesized in situ.
The synthetic utility of isoureas is not limited to ester
formation.10,13
Isourea-mediated ester formation method has several advan-
tages over the traditional carbodiimide-mediated coupling of
an alcohol with a carboxylic acid. For example, the formation
of O-acylisoureas, which are unstable structures that can undergo
isomerization to the corresponding N-acylureas, is avoided.1j,14
Kappe has shown that microwave-assisted solid-phase coupling
using this method mainly led to the rearranged N-acylureas.15
In addition, activation of R-chiral carboxylic acids also intro-
duces a racemization or epimerization risk (this is more
prominently the case in peptide synthesis where the formation
of an oxazolone intermediate is possible).14 The chemoselec-
tivity of the O-alkylisourea-mediated ester formation is very
good because alcohols16 and even phenolic groups17 do not react
with these reagents under normal reaction conditions. An
attractive feature for the isourea-mediated ester formation is that
no additional reagent or catalyst (acid, base) is required for the
reaction. Moreover, the reaction occurs with inversion of
configuration18 and is thus a potential alternative to the
The reaction of carboxylic acids 2 (Scheme 1) with O-
alkylisoureas 1 to give the corresponding alkyl esters 3 is
well-established.10,11 O-Alkylisoureas are easily prepared by the
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