Tetrahedron Letters
Chromatography-free, Mitsunobu-triggered heterocyclizations of
salicylhydroxamic acids to 3-hydroxybenzisoxazoles
Daniel Van Eker a, Jay Chauhan b, William A. Murphy c, Ivie L. Conlon b, Steven Fletcher b,d,
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a School of Chemistry, University of Cardiff, Cardiff CF10 3AT, UK
b Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, United States
c PharmD Program, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, United States
d University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The Mitsunobu reaction has become one of the most powerful tools to alkylate acidic pronucleophiles. A
significant caveat of Mitsunobu chemistry, however, is that the reaction mixture is often plagued with
purification problems owing to the phosphine oxide and hydrazine dicarboxylate by-products. In addi-
tion to the development of more readily separable Mitsunobu reagents, the product’s physicochemical
properties may be exploited to facilitate purification. In this regard, we present a swift and efficient
preparation of 3-hydroxybenzisoxazoles by the Mitsunobu-triggered heterocyclizations of salicylhydrox-
amic acids, which can be isolated by an acid–base work-up. As expected, a range of functional groups was
compatible with the chemistry.
Received 16 August 2016
Revised 7 October 2016
Accepted 12 October 2016
Available online xxxx
Keywords:
Mitsunobu reaction
Salicylhydroxamic acid
3-Hydroxybenzisoxazole
Bioisostere
Ó 2016 Elsevier Ltd. All rights reserved.
Dehydrative-heterocyclization
Bioisosterism is the replacement of key functional groups with
moieties that result in safer and/or clinically more effective drugs.1
During our research program on the development of inhibitors of
the Mcl-1 oncoprotein,2 we explored the replacement of an
arenecarboxylic acid motif, that is proposed to capture Arg263
through a salt bridge, with various bioisosteres to promote cell
penetration. Bearing pKa’s of around 5,3 3-hydroxybenzisoxazoles
represent a potential surrogate for arenecarboxylic acids. Typically,
3-hydroxybenzisoxazoles are prepared by cyclizations of the corre-
sponding salicylhydroxamic acids with carbonyl diimidazole in
refluxing THF,4 although the range of yields associated with this
chemistry would suggest it to be rather capricious. We considered
if a milder and more reliable approach to these target molecules
could be developed.
The Mitsunobu reaction is a powerful tool to alkylate acidic
pronucleophiles through the in situ activation of primary and sec-
ondary alcohols, and occasionally tertiary alcohols, upon the reac-
tion of a phosphine, typically triphenylphosphine (PPh3), with an
azodicarboxylate, typically diisopropyl azodicarboxylate (DIAD).5,6
Suitable pronucelophiles exhibit pKa’s<12, and include carboxylic
acids, phenols, sulfonamides,6 as well as various heterocycles, such
as purines,7 benzodiazepine-2,5-diones,8 and 3-hydroxyisoxa-
zoles.9 The chemistry is highly versatile featuring in the construc-
tion of CAO, CAS, CAN, and CAC bonds.6 Moreover, the reaction is
mild, often occurring in under an hour at room temperature, and is
tolerant of a wide range of functional groups. However, despite all
these highlights, this chemistry is marred by the often problematic
purification owing to the attendant phosphine oxide and hydrazine
dicarboxylate generated in the reaction. Many groups, including
ours, have developed alternative phosphine and azodicarboxylates
to facilitate purification of the reaction mixture.6,10–12 In parallel
with this, the product’s physicochemical properties may be
exploited to facilitate purification. Recently, we reported on the
Mitsunobu-triggered dehydration of salicylaldoximes to generate
salicylonitriles via the corresponding benzisoxazoles.13 Due to
their acidities, the products were isolable by acid–base work-ups
without the need for column chromatography. Herein, we present
the Mitsunobu-triggered heterocyclizations of salicylhydroxamic
acids to 3-hydroxybenzisoxazoles that can likewise be isolated
by an acid–base work-up.
We considered that salicylhydroxamic acid carries all the ele-
ments for a successful Mitsunobu reaction, i.e. an acidic nucle-
ophile (phenol moiety) and an alcohol (hydroxamic acid
hydroxyl). Indeed, a lone report on the heterocyclization of salicyl-
hydroxamic acid into its corresponding 3-hydroxyisoxazole by the
Mitsunobu reaction exists, although no conditions, yield, nor work-
up/purification were provided.14 Furthermore, no exploration into
the substrate scope was presented. In our hands, treatment of sal-
icylhydroxamic acid 1 with 1.25 equiv of both PPh3 and DIAD in
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Corresponding author. Tel.: +1 410 706 6361.
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.