Zn(OAc)2 · 2H2O-catalyzed, simple, and clean procedure for the synthesis of 2-substituted benzoxazoles using a grindstone method

Article abstract of DOI:10.1080/00397911.2010.493260

Zn(OAc)₂ · 2H₂O efficiently catalyzes the condensation reaction between 2-aminophenol and various araldehydes to afford the 2-substituted benzoxazoles in good to excellent yields. The remarkable features of this protocol are simple and mild reaction conditions, use of readily available catalyst, and shorter reaction time, and in addition the reaction proceeds just by grinding the substrates and catalyst without any solvent and hence matches the green chemistry protocols.

Full text of DOI:10.1080/00397911.2010.493260

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Zn(OAc)2 · 2H2O-Catalyzed, Simple,
and Clean Procedure for the Synthesis
of 2-Substituted Benzoxazoles Using a
Grindstone Method
M. B. Madhusudana Reddy a , Aatika Nizam a & M. A. Pasha a
a Department of Studies in Chemistry, Central College Campus,
Bangalore University, Bengaluru, India
Version of record first published: 29 Apr 2011
To cite this article: M. B. Madhusudana Reddy, Aatika Nizam & M. A. Pasha (2011): Zn(OAc)2 · 2H2O-
Catalyzed, Simple, and Clean Procedure for the Synthesis of 2-Substituted Benzoxazoles Using a
Grindstone Method, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 41:12, 1838-1842
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Synthetic Communications1, 41: 1838–1842, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.493260
Zn(OAc)2 Á 2H2O-CATALYZED, SIMPLE, AND CLEAN
PROCEDURE FOR THE SYNTHESIS OF 2-SUBSTITUTED
BENZOXAZOLES USING A GRINDSTONE METHOD
M. B. Madhusudana Reddy, Aatika Nizam, and M. A. Pasha
Department of Studies in Chemistry, Central College Campus, Bangalore
University, Bengaluru, India
GRAPHICAL ABSTRACT
Abstract Zn(OAc)2 Á 2H2O efficiently catalyzes the condensation reaction between
2-aminophenol and various araldehydes to afford the 2-substituted benzoxazoles in good
to excellent yields. The remarkable features of this protocol are simple and mild reaction
conditions, use of readily available catalyst, and shorter reaction time, and in addition
the reaction proceeds just by grinding the substrates and catalyst without any solvent and
hence matches the green chemistry protocols.
Keywords 2-Aminophenol; araldehydes; benzoxazoles; grindstone method; solvent-free
condition; Zn(OAc)2 Á 2 H2O
INTRODUCTION
Synthesis of 2-substituted-benzoxazoles has attracted interest in diverse areas
of chemistry.[1] These heterocycles have shown different pharmacological activities
such as antiviral,[2] antimicrobial,[3] anti-Parkinson,[4] anticancer,[5] and antibiotic[6]
properties. The benzoxazole scaffold is also found in many biologically active
compounds such as elastase inhibitors[7] and H2 antagonists.[8]
Synthetic routes to get 2-substituted benzoxazoles typically involve direct
coupling of a carboxylic acid or carboxylic acid derivatives with 2-aminophenol in
the presence of a strong acid at high temperature. A two-step procedure is also
developed in which 2-aminophenol is treated with 1equivalent of an acid chloride,
and the resulting mono-N-acylated-2-aminophenol is then treated with a variety of
reagents including carboxylic acids,[9] orthoesters,[10] acid chlorides,[11] nitriles,[12]
Received January 22, 2010.
Address correspondence to M. A. Pasha, Department of Studies in Chemistry, Central College
Campus, Bangalore University, Bengaluru 560 001, India. E-mail: m_af_pasha@ymail.com
1838

BENZOXAZOLE SYNTHESIS BY GRINDING
1839
Scheme 1. Zinc acetate–catalyzed synthesis of benzoxazoles.
amides,[13] aldehydes,[14] or esters.[15] Beckmann rearrangement of 2-acylphenol oxi-
mes[16] and photocyclization of phenolic Schiff bases[17] are also used for their syn-
thesis. A few pyrolytic methods for the conversion of diacylated-2-aminophenols
into 2-substituted-benzoxazoles also appear in the literature.[18] Benzoxazoles have
normally been synthesized in nonpolar high-boiling solvents such as toluene and
xylene[19] in polar solvents with high boiling points (e.g., sulfolane), and in other
solvents such as dichloroethane, dichlorobenzene, and 1,4-dioxane.[20] It is well
known that the solvents used are hazardous, and all these procedures require
stoichiometric or excess amounts of reagents to effect the reactions. Many of the pro-
cedures produce toxic or environmentally problematic by-products, often involve
laborious workup procedures, and=or suffer from poor yields. Therefore, develop-
ment of more convenient, environmentally friendly, and practical synthetic methods
for benzoxazoles still remains an active area of research.
In continuation of our work to explore the utility of simple, one-pot,
solvent-free, and solid-phase grinding method (the grinding method has been used
by us in the synthesis of biologically important bis(indolyl)methanes[21] and
4-arylidine-2-phenyl-5(4H)-oxazolones[22]), we have synthesized benzoxazoles by
grinding 2-aminophenol with various araldehydes in the presence of Zn(OAc)2 Á
2H2O as catalyst (Scheme 1).
RESULTS AND DISCUSSION
By grinding thoroughly a mixture of 2-aminophenol with various araldehydes
in the presence of Zn(OAc)2 Á 2H2O using a pestle and mortar at room temperature in
an open atmosphere, benzoxazoles were formed in excellent yield within 5 min. To
ascertain the optimum conditions, a series of preliminary experiments were carried
out using anisaldehyde as model substrate; the reactants were initially ground
without any catalyst, but no formation of the product was observed. Then, we
decided to use a catalyst, and a number of acidic catalysts were tried for the purpose.
When Zn(OAc)2 Á 2H2O was employed, we got very good results.
Encouraged by these preliminary results, we explored the possibility of gener-
ating a small library of benzoxazoles, and the results are presented in Table 1. From
Table 1, it is clear that both aldehydes bearing electron-donating groups (entries 2–4
and 8–10) and electron-withdrawing groups (entries 6–8) gave corresponding ben-
zoxazoles in good to excellent yields (84–95%). The structures of all the products
were determined from their spectroscopic data, by comparison of the physical

1840
M. B. M. REDDY, A. NIZAM, AND M. A. PASHA
Table 1. Synthesis of 2-substituted-benzoxazolesa
Entry
Aldehyde (2)
Productb
Time (min)
Yield (%)
1
2
C6H5CHO
3a
3b
3c
3d
3e
3f
4
3
4
5
4
5
5
4
3
4
4
5
92
95
87
85
92
90
95
89
89
90
84
87
4-MeO-C6H4CHO
2-MeO-C6H4CHO
4-Me-C6H4CHO
3-Me-C6H4CHO
2-NO2-C6H4CHO
4-Cl-C6H4CHO
2,4-Cl2-C6H3CHO
4-NH2-C6H4CHO
4-HO-C6H4CHO
2-HO-C6H4CHO
Furyl-CHO
3
4
5
6
7
3g
3h
3i
8
9
10
11
12
3j
3k
3l
aReaction condition: Aldehyde (1 mmol), 2-aminophenol (1 mmol), and Zn(OAc)2 Á 2H2O (0.5 mmol)
were ground using a pestle and mortar at rt until the overall mixture turned into a solid.
bYields refer to pure isolated products.
Scheme 2. Plausible mechanism for the formation of benzoxazoles.
constants, and on thin-layer chromatography with the samples prepared by the
reported methods.
The mechanism of the reaction most likely involves the prior formation of an
intermediate imine (A), which may undergo cyclization with the o-hydroxyl group
present in the 2-aminophenol to give 2-substituted-2,3-dihydro-benzoxazole (B),
which by aerial oxidation yield benzoxazoles (4) as shown in Scheme 2.
EXPERIMENTAL
All chemicals used were commercial, and all solvents were distilled before use.
Melting points were recorded in open capillaries using a paraffin bath, and corrections
are applied wherever necessary. The products were characterized by comparison of
1
their physical data or from their infrared (IR), H NMR, and gas chromatography

BENZOXAZOLE SYNTHESIS BY GRINDING
1841
(GC)–mass spectra with those of known samples. The IR and 1H NMR spectra of the
products were recorded on Shimatzu Fourier transform (FT)–IR 8400 s and Bruker
AMX (400-MHz) spectrometers respectively. Yields refer to the isolated yields of
the products. GC–mass spectra were obtained using a Shimadzu GC-MS QP 5050A.
General Procedure for the Preparation of 2-Substituted
Benzoxazoles
A
mixture of araldehyde (1 mmol), 2-aminophenol (1 mmol), and
Zn(OAc)2 Á 2H2O (0.5 mmol, 0.104 g) was thoroughly ground with a pestle in a mor-
tar at room temperature in an open atmosphere until the overall mixture turned into
a solid. Grinding was continued until the reaction went to completion (progress of
the reaction was monitored by TLC). After completion, the solid was washed with
water, and the product was crystallized from rectified spirit or purified by column
chromatography using a short silica-gel column.
CONCLUSION
In conclusion, we report a high-yielding, one-pot protocol for the synthesis of
benzoxazoles from readily available and inexpensive materials. The valuable features
of this method include (i) mild reaction conditions, (ii) a wide range of functional
groups are tolerated, (iii) solvent-free reaction, thereby making the purification pro-
cess simple, and (iv) elimination of solvent waste.
As the reactions work by grinding the reactants and the catalyst, there is scope
for use of ball mills in the future for preparing benzoxazoles on a large scale.
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