E. Rancan et al.
unwanted by-products or wastes, being the latter a typical
consequence of the multi-workup operations [2].
process, it is crucial to find an economically convenient use
of 2-hydroxyacetophenone being a byproduct obtained in
non negligible amount [16–19].
Heterocycles such as indoles and benzoxazoles are
interesting intermediates for a wide variety of products
ranging from herbicides, optical brighteners, to drugs and
pharmaceutical, corrosion inhibitors, intermediates in
general [3, 4].
It is noteworthy that an electrophilic attack to the phenyl
ring of 2-hydroxyacetophenone is favored due to the acti-
vation of the hydroxyl group, thus allowing a wide range of
products to be used as intermediates for fine and/or
medicinal chemistry [20].
As an example, in the last 10 years several investiga-
tions have been reported on benzoxazole-based chemo-
therapics [5–8]. In particular, medicinal chemistry
applications of benzoxazoles include anticancer agent [9]
and drugs for Alzheimer’s disease [10]. Studies conducted
on this class of heterocycles indicate that their wide range
of biological activities derive from oxazoles moiety [11].
Typically oxazoles are synthesized by multistep reaction
involving as starting reagents o-aminophenols, usually
obtained by nitration of phenols and successive reduction
of the corresponding nitro-compound [12]. The synthesis
of oxazole via aminophenols is well known and it involves
acid or base catalyzed condensation reaction with alde-
hydes, nitriles, BrCN, ClCOAr and in general with other
carbonyl electrophiles [13, 14]. Other synthetic paths,
which use as reagents 2-Br-anilines and/or di-halogen-aryl
compounds, have been also reported, although they still
involve multistep procedures [13].
Among the products that can be obtained from 2-hy-
droxyxaril aldehyde and ketones, benzoxazoles are the
ones that can be synthesized in high yield from the corre-
sponding aldoximes and ketoximes via a two step reaction:
(1) Beckmann rearrangement, (2) dehydration-cyclization
(see Scheme 1) [3, 21, 22].
We have already reported Beckmann rearrangement of
various oximes by using TFA as organocatalyst focusing
on its applications for the high yielding synthesis of amides
[23–26]. Recently, also Luo and coworkers have studied
the reactivity of TFA in the Beckmann rearrangement of
cyclohexanone oxime obtaining similar results [27–30]. In
particular, in our case study, caprolactam, acetanilide and
other amides were synthesized from the corresponding
ketones in neat by using TFA as solvent–catalyst and
hydroxylamine hydrochloride [30]. The reaction proceeds
in one-pot by oximation and Beckmann rearrangement of
the ketones to the corresponding amides by following a
two-stages mechanism whose kinetics is influenced by
ketones structure [29, 30]. Furthermore, recently, we
investigated the reaction between ketones and NH2OHÁHCl
in the absence of acid catalyst, where we demonstrated an
autocatalytic effect of the HCl released after the nucleo-
philic attack of NH2OH to carbonyl group of ketones [30].
In these reactions the role of the solvent is of paramount
importance to achieve good yield and selectivity, as well as
that of temperature. As a matter of fact, the balance of
these reaction parameters allows high amide yield.
On the light of these findings, we postulated that benz-
oxazole could be synthesized using 2-hydroxyacetophe-
nones as building block via Beckmann rearrangement of
the corresponding oximes.
Therefore, a versatile pool of starting materials is
available for a large range of benzoxazole products, how-
ever, multistep approaches and the use of expensive
building blocks limit the sustainability of the synthesis
from both environmental and economic point of view [13].
In this context we report for the first time a new syn-
thetic strategy to benzoxazoles starting from 2-hydroxy-
acetophenone, a cheap reagent since large amounts of this
ketones are available from Fries rearrangement of aril
acetates, a widely employed reaction in fine chemistry [15–
17].
In fact, it is well known, that the selectivity of Fries
rearrangement of phenyl acetate to 4-hydroxyacetophe-
none, which is the key intermediate in the acetaminophen
manufacture via Hoechst–Celanese process, reaches about
90–94 % of selectivity to the 4-position [18]. The main by-
product formed is the isomer 2-hydroxyacetophenone,
which has limited application as chelating agent for metal
recovery or as intermediate in fine chemistry [19].
In Fries rearrangement, though solvent and catalyst play
important roles, the control of the ortho/para ratio is
mainly determined by temperature that is at high temper-
ature (165 °C) the ortho isomer is favored, while at low
temperature (25 °C) the para is the preferred one. In any
case, the selectivity towards one of the two isomers is
never complete, at most 90–95 % selectivity can be
reached [16–18]. For this reason, in order to improve the
efficiency and the sustainability of the Hoechst–Celanese
So far, only one example of the one-step synthesis
of benzoxazole via oximation-Beckmann rearrangement-
dehydrocyclization of 2-hydroxyaryl ketones has been
reported. However, this reaction was carried out in the
presence of mineral acid and by microwave irradiation,
being this procedure neither industrially convenient nor
environmentally benign [31].
Therefore, in this work we report on a new procedure for
the catalytic synthesis of benzoxazoles employing 2-hy-
droxyacetophenones as building block for heterocycles of
industrial interest by using hydroxylamonium salts as am-
idation agent. The synthesis proceeds via a catalytic direct-
amidation–dehydrocyclization, which gives benzoxazoles
123