Research Article

pubs.acs.org/journal/ascecg

Methods for the Direct Synthesis of Benzoxazoles from Halogenated

Nitriles in Alcoholic Solvents
Roy P. Lester and Jason E. Camp*
School of Chemistry, University of Nottingham, Nottingham NG7 2RD, U.K.
*
S Supporting Information

ABSTRACT: Two complementary approaches for the direct

synthesis of 2-dichloro- and 2-trichlorobenzoxazoles from 2-
aminophenols and halogenated nitriles are reported. A green,
noncatalyzed method was shown to proceed in an alcoholic
solvent without the addition of exogenous acid or base. This
method provides a clean and robust synthesis of these
important heterocycles, which contain a key functional group
handle at the 2-position. A complementary platinum multifaceted catalysis approach was also developed in which the metal can
catalyzes multiple mechanistically distinct processes. This method allows for an improved use of the metal catalyst vs stepwise
protocols and provides increased flexibility in the choice of reaction conditions.
KEYWORDS: Green chemistry, Alcoholic solvent, Platinum catalysis, Heterocycle, Multifaceted catalysis

■ INTRODUCTION
Benzoxazoles are a useful class of heterocycle that have found
removed under reduced pressure and the residue was purified by flash
column chromatography on silica gel (3% ethyl acetate in petroleum
ether) to afford the trichlorobenzoxazole.

■
prominence in the area of medicinal and agricultural
chemistry.1−5 Due to the preponderance of this motif in
biologically active compounds, a number of methods have been RESULTS AND DISCUSSION
developed for their synthesis6−8 and functionalization.9 One In search of a suitable transition metal catalyst to facilitate a
underutilized method of benzoxazole formation is via the metal-catalyzed synthesis of benzoxazoles, simple platinum salts
reaction of 2-aminophenols with nitriles.10 Nitriles have been were screened17 in the reaction of 2-aminophenol (1a) with
used extensively in the synthesis of heterocyclic compounds, trichloroacetonitrile (Table 1, entry 1). Initially, platinum(II)
though they are traditionally activated for nucleophilic addition chloride was found to be effective in generating 2-
by the application of strong protic acids11 or Lewis acids12 with trichlorobenoxazole 2a from the reaction of 2-aminophenol
a small number of alternative methods recently developed.13−16 (1a) and trichloroacetonitrile in the nonpolar solvent n-hexane.
Many of these methods though require harsh reaction Previously, it had been shown that primary aliphatic amines do
conditions and toxic additives leading to high levels of waste.
Therefore, there remains a demand for increasingly efficient
Table 1
methods for the convergent synthesis of benzoxazoles from
simple, readily available starting materials. Encouraged by the
potential applications of substituted benzoxazoles, greener
approaches to their direct formation from halogenated nitriles
were investigated. Herein, is described the development of both
a platinum-catalyzed method and a catalysts free method in
entry solvent (1 M) catalyst (10 mol %) temp (°C) yield (%)a
methanol for the direct synthesis of 2-dichloro and 2-trichloro
substituted benzoxazoles from halogenated nitriles. 1 n-hexane PtCl2 80 72

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2 n-hexane PtCl4 80 82
EXPERIMENTAL SECTION 3 n-hexane 80 0
4 EtOH PtCl4 80 64
General Procedures. Platinum-Catalyzed. To a stirred suspen-
5 EtOH 80 99
sion of PtCl4 (10 mol %) and 2-aminophenol (1 equiv) in n-hexane (1
M) at rt was added trichloroacetonitrile (2.2 equiv). The resultant 6 EtOH 40 98
mixture was stirred at 80 °C for 19 h. The solvent was removed under 7 MeOH 40 99
reduced pressure and the residue was purified by flash column a
Isolated yield.
chromatography on silica gel (3% ethyl acetate in petroleum ether) to
afford the benzoxazole.
Catalyst Free. To a solution of 2-aminophenol (1 equiv) in Received: January 31, 2013
methanol (1 M) at rt was added trichloroacetonitrile (1.1 equiv). The Revised: March 7, 2013
resultant mixture was stirred at 40 °C for 19 h. The solvent was Published: March 26, 2013

© 2013 American Chemical Society 545 dx.doi.org/10.1021/sc4000253 | ACS Sustainable Chem. Eng. 2013, 1, 545−548
ACS Sustainable Chemistry & Engineering Research Article

no react with trichloroacetonitrile in nonpolar solvents in the Scheme 1

absence of a catalyst.18 After minimal experimentation,19 it was
found that the reaction proceeded in the highest yield when run
in n-hexane at 80 °C in the presence of 10 mol % platinum(IV)
chloride (Table 1, entry 2). Importantly, none of the desired
benzoxazole 2a was observed in the absence of the catalysts
(Table 1, entry 3). As part of a screen utilizing more
environmentally friendly solvents,20,21 it was found that the
protic solvent ethanol was also a viable solvent for the
platinum-catalyzed process.19 Interestingly, when the control
reaction was run in the absence of the platinum species a near
quantitative yield of benzoxazole 2a was isolated (Table 1,
entry 4 vs 5).22 Subsequently, it was found that after 19 h the
reaction between aminophenol (1a) and trichloroacetonitrile to
give benzoxazole 2a at temperatures down to 40 °C in either
ethanol or methanol proceeded in good yield. Decreased yields
were observed when the time of the reaction was reduced.
Thus, two viable methods for the direct synthesis of 2-
trichlorobenzoxazoles were developed. Importantly, these
methods are complementary and allow for flexibility with
regards to polar protic or nonpolar aprotic solvents, which have
implications on both downstream processing and the potential
for further tandem transformations.
Due to the high price and limited amounts of transitions
metals for catalysis23 and issues surrounding the use of
hydrocarbon solvents,24 we decided to focus on the more
sustainable noncatalyzed process in alcoholic solvents. Owing a
PtCl4 (10 mol %), n-hexane, 80 °C, 19 h. b2.2 equiv of Cl3CCN was
to its high yield of product as well as increased workers’/ used.
process safety and decreased environmental impact verses
traditional organic solvents,20,21 methanol was chosen as the Next the reaction between aminophenols 1 and the less
solvent for the direct formation of benzoxazoles from activated nitrile, dichloroacetonitrile, to form 2-dichlorobenzox-
halogenated nitriles. With the choice of solvent in hand, the azoles 3 was investigated. The product dichlorobenzoxazoles 3
scope of the catalyst free method for the direct formation of are potentially useful compounds as alkylating reagents33 and as
benzoxazoles was investigated. It was found that aryl- masked aldehydes.34 Reaction of aminophenol 1a with
substituted and fused aminophenols gave the corresponding dichloroacetonitrile in methanol at 40 °C afforded the desired
benzoxazoles 2b,c in good yields when reacted with 2-dichlorobenzonitrile 3a in good yield (Scheme 2). In
trichloroacetonitrile at 40 °C in methanol (Scheme 1).
Additionally, alkyl substituted aminophenols and electron rich Scheme 2
methoxy derivatives gave the expected benzoxazoles 2d−g in
good yield. Importantly, halogenated aminophenols formed the
corresponding benzoxazoles 2i−k, which contain a functional
group handle for further cross-coupling transformations.25,26
Finally, it was found that bis-benzoxazole 2l could be formed
from the corresponding bis-aminophenol in good yield by
increasing the amount of trichloroacetonitrile to 2.2 equiv.
Unfortunately, aminophenols with strongly electron with-
drawing groups, such as nitro and carboxylic acids moieties
did not afford any of the desired benzoxazoles and only the
starting materials were recovered. A number of the amino-
phenol substrates were also subjected to the platinum-catalyzed
conditions. For example, the platinum-catalyzed reaction of
aminophenol 1b with Cl3CCN in n-hexane at 80 °C afforded
the desired benzoxazole 2b in 20% yield. In all of the cases
a
examined, a lower isolated yield of the benzoxazole products 4.0 equiv of dichloroacetonitrile was used.
was observed in comparison to the methanol conditions. The
platinum-catalyzed process though may be applicable to contrast, subjection of these reagents to the platinum-catalyzed
systems that require aprotic conditions or in which further conditions only afforded 2-dichlorobenzonitrile 3a in 31% yield.
tandem processes facilitated by the platinum are desired.27 The scope of the methanol reaction was also explored and it
Additionally, the product trichlorobenzoxazoles are useful was found that methylated 3d, halogenated 3i,j, and bis-
substrates for further functionalization as the trichloro moiety benzoxazole 3l could be synthesized in good yields. The yields
can be converted into a variety of other functional groups28−30 of the 2-dichlorobenzoxazoles 3 were approximately 20% lower
or directly displaced by a nucleophile.31,32 than the corresponding 2-trichloro compounds 2, except in the
546 dx.doi.org/10.1021/sc4000253 | ACS Sustainable Chem. Eng. 2013, 1, 545−548
ACS Sustainable Chemistry & Engineering

■
Research Article

case of bis-benzoxazole 3l, which was formed in the same ACKNOWLEDGMENTS

isolated yield as 2l. We thank the School of Chemistry at the University of
Mechanistically, we believe that the both the platinum- Nottingham and the EPSRC (First-Grant EP/J003298/1) for
catalyzed and the uncatalyzed methanol conditions proceed supporting the research as well as Dr. Jay J. Dunsford for
through similar amidine intermediates 4/6 (Scheme 3).35 helpful discussion.

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Corresponding Author
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548 dx.doi.org/10.1021/sc4000253 | ACS Sustainable Chem. Eng. 2013, 1, 545−548