Article
DOI: 10.1002/bkcs.12138
BULLETIN OF THE
G.-T. Kwon et al.
KOREAN CHEMICAL SOCIETY
Choline Hydroxide as a Versatile Medium for Catalyst-Free
O-Functionalization of Phenols
Gyu-Tae Kwon,† Seong-Ryu Joo,† Soo-Youl Park,‡ and Seung-Hoi Kim†,
*
†Department of Chemistry, Dankook University, 119 Dandaero Cheonan, Korea 31116.
*E-mail: kimsemail@dankook.ac.kr
‡Korea Research Institute of Chemical Technology, Daejeon, Korea 34114
Received August 8, 2020, Accepted October 21, 2020
A versatile synthetic protocol for benzyl phenyl ether preparation via O-alkylation of phenolic oxygen
with readily available benzyl derivatives was demonstrated. The newly designed procedure was carried
out using an eco-friendly medium, room-temperature ionic liquid (choline hydroxide), under metal- and
base-catalyst-free aerobic conditions. The reaction platform was also successfully applied to phenol pro-
tection strategy.
Keywords: Choline hydroxide, Phenols, O-alkylation, Benzyl phenyl ether, Catalyst-free coupling
Introduction
the hydroxyl group of phenol in the presence of Hünig’s
base (N,N-diisopropylethylamine) without the use of sol-
vent.6 Recently, phase-transfer-catalyst (t-butyl ammonium
bromide)-mediated benzylation of phenols with an inor-
ganic base in water was successfully achieved by Wu
et al.7 More eco-friendly media, room-temperature ionic
liquids (RTILs), were also used for the benzylation of phe-
nols by Nagarkar et al.8 In their study, benzylation using
choline chloride (ChCl)-based task-forced DES (deep
eutectic solvent), which consisted of ChCl, urea, and KOH,
was achieved. It is of interest that choline hydroxide, a
basic IL, has attracted much attentions in synthetic chemis-
try due to its unique properties.9
Given our previous successful study on functional group
transformation using choline hydroxide (ChOH) as a reac-
tion medium,10 we have conducted further investigations
on the development of a versatile synthetic route for O-
alkylation of phenolic substrates using an environment-
friendly reaction condition.
Phenolic derivatives are one of the most frequently founded
motifs in natural organic compounds.1 More importantly,
their functionality has played a crucial role in biologically
active materials. Therefore, tremendous efforts have been
devoted to the preparation and application of phenolic com-
pounds in academic and industrial chemistries. Given the
sustainable feature of phenols, it is highly desirable to
develop a facile strategy to diversify their applicability.
In general, phenol derivatives have been provided with
either C- or O-functionalization of phenol rings, depending
on the chemoselectivity of C- vs. O-substitution, which is
in turn highly dependent on the conditions employed.2
Therefore, it has been recognized that the selective func-
tionalization of phenols has long been a challenging subject
for the development of more affordable protocols for high
chemoselectivity with the obtained phenolic derivatives
being frequently utilized as building blocks or bioactive
materials in a wide range of chemical industries and aca-
demic researches.3
Results and Discussion
It is also of interest that the O-alkylation or arylation
pathway of phenols has been considered a versatile strategy
for not only the construction of phenolic compounds but
also the protection of their hydroxyl group.4 Because
protecting a certain functional group is one of the inevitable
tools in multistep organic synthesis, development of versa-
tile phenol protection protocols has attracted much research.
Of several approaches employed to date, benzylation of
phenolic oxygen has been widely utilized due to the easy
accessibility of benzyl halides.
Initially, phenol (1a) was reacted with 2.0 equivalents of
benzyl bromide (2a) in aqueous ChOH, and, to our delight,
the coupling reaction proceeded smoothly, furnishing the
desired benzyl phenyl ether (3a) in a satisfactory manner.
Other results and conditions for optimization of the cou-
pling reaction employing various parameters are summa-
rized in Table 1.
Based on the result (70% isolated yield of 3a) from the
initial attempt carried out in the absence of any metal- and
additional base-catalyst at room temperature, further tests to
optimize the reaction parameters have been carried
out. Increased reaction temperature of up to 45 ꢀC was
applied, resulting in disappointed product yield (entry 2).
In this context, since the first report of O-benzylation of
phenol by McKillop,5 this approach has been performed in
various reaction conditions. In addition to the traditional
methodologies, Maki’s group reported the benzylation of
Bull. Korean Chem. Soc. 2020
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