CL-141127
Received: December 7, 2014 | Accepted: December 28, 2014 | Web Released: January 8, 2015
Straightforward Synthesis of 2-Anilinobenzoxazoles and -benzothiazoles
via Mechanochemical Ball-milling-promoted One-pot Reactions
Ze Zhang,* Fang-Jian Wang, Hao-Hao Wu, and Ya-Jun Tan
School of Biological and Chemical Engineering, Anhui Polytechnic University, Wuhu 241000, P. R. China
(E-mail: zhangze@ustc.edu.cn)
Under mechanochemical ball-milling and solvent-free con-
Table 1. One-pot synthesis of 2-anilinobenzoxazoles 3 cata-
lyzed by FeCl3 under ball millinga
ditions, a series of 2-anilinobenzoxazoles and -thiazoles were
synthesized directly from the one-pot reaction of anilines, CS2,
and 2-aminophenol and -thiophenol. This protocol exhibits the
following advantages: free or cheap use of a cyclodesulfuriza-
tion reagent, no separation of in situ generated isothiocyanate,
short reaction time, and simple work-up procedure.
NH2
NCS
CS2, KOH
R
R
Mechanical Milling
Time 1
1
2
(in situ)
OH
Anilinobenzoxazoles and anilinobenzothiazoles have been
attracting much attention due to their important structural motifs
in medicinal chemistry.1,2 Due to their great importance,
considerable efforts have been made for the efficient construc-
tion of these units. Up to now, a large variety of synthetic
methods have been documented.3 These methods are generally
efficient and high yielding, but most cases suffer from an
expensive catalyst, drastic reaction conditions, pre-made starting
materials such as toxic and unstable isothiocyanates, high
temperatures, relatively long reaction times, or tedious purifica-
tion work up. To circumvent these problems, mechanochemical
ball milling, a powerful and greener way for the efficient
promotion of various organic reactions,4,5 may be an effective
alternative. On the other hand, there are facts that: (a) cyclo-
desulfurization of the intermediates generated by 2-amino-
phenols and -thiophenols with isothiocyanates can afford 2-
aminobenzoxazoles and -thiazoles efficiently;6,7 (b) anilines
can be smoothly transformed into isothiocyanates under high-
speed ball milling.8 Therefore, we explored and herein wish to
report a solvent-free method for the one-pot synthesis of these
compounds via the addition and cyclodesulfurization of 2-
aminophenol or 2-aminothiophenol, with in situ generated
isothiocyanates from anilines and CS2 using the ball-milling
technique.
After various attempts (see Supporting Information), FeCl3
was optimized as the cyclodesulfurization catalyst for extension
studies, considering its best efficiency, easy availability, low
price, sustainability, nontoxicity, and environmentally friendly
properties.9 Usage of 0.25 molar equivalent is enough to
promote the transformation completely. As outlined in Table 1,
a series of 2-anilinobenzoxazoles were successfully synthesized
in good to excellent yields from the corresponding anilines
bearing either electron-donating or electron-withdrawing groups.
In contrast, it is more efficient for anilines bearing electron-
donating groups, which are easier to transform into the
corresponding isothiocyanates 2. However, when isothiocya-
nates 2 were formed, the addition-cyclodesulfurization process
was accomplished more rapidly for cases involving electron-
withdrawing groups (Entries 4-6). Furthermore, it is worthy to
point out that all the products were obtained through a very
simple work up, just including washing the resulting reaction
mixture with water and recrystallization in EtOH/H2O, without
O
N
NH
NH2
.
FeCl3 6H2O
R
Mechanical Milling
Time 2
3
Time 1 Time 2 Yield
Entry
R
H
4-Me
4-OMe
4-Cl
Product 3
/min
/min
/%b
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
60
40
40
70
70
90
60
90
90
60
60
60
79
87
90
82
84
72
4-Br
2-Cl
aReactions were carried out with aniline 1 (2.0 mmol), CS2
(10.0 mmol), KOH (2.0 mmol), afterward added 2-amino-
phenol (2.0 mmol) and FeCl3¢6H2O (0.5 mmol) under ball
milling at room temperature with a vibration frequency of
b
30 Hz. Isolated yield combined from two parallel runs.
the need for isolation of in situ generated isothiocyanates 2 or
any column chromatography work.10
Next, this strategy was extended to the synthesis of 2-
anilinobenzothiazoles 4 using 2-aminothiophenol instead of 2-
aminophenol. To our delight, in these cases, various desired
products were still efficiently obtained even without using any
cyclodesulfurization reagents (Table 2). This higher efficiency
may be ascribed to the fact that thiophenol has stronger acidity,
which would result in easier cyclodesulfurization.
In summary, a straightforward and environmentally friendly
method for the direct transformation of various anilines into the
corresponding 2-anilinobenzoxazoles or 2-anilinobenzothiazoles
has been successfully developed using the mechanochemical
ball-milling technique. This protocol exhibits several promising
advantages including the use of cheap FeCl3 or even no using
cyclodesulfurization catalyst, simple isolation work up, no need
of pre-made toxic and unstable isothiocyanates, which make it a
very efficient, economical, and practical alternative to traditional
methods for the synthesis of this kind of compound.
© 2015 The Chemical Society of Japan