Pd(OAc)2 catalyzed synthesis of 2-aryl- and 2-heteroaryl- benzoxazoles and benzothiazoles in imidazolium ionic liquids (ILs) without additives and with recycling/reuse of the IL

Article abstract of DOI:10.1016/j.tetlet.2012.05.155

A facile, high yielding, method for the synthesis of a library of 2-aryl- and 2-heteroaryl-benzoxazoles and benzothiazoles from readily available Schiff bases is reported employing catalytic amounts of Pd(OAc)₂ in imidazolium ionic liquids (bmim)BF₄ and (bmim)PF₆ without ligands and/or additives. Simple product isolation and recycling/re-use of the IL are additional advantages of this method.

Full text of DOI:10.1016/j.tetlet.2012.05.155

Tetrahedron Letters 53 (2012) 4212–4215
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Tetrahedron Letters
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Pd(OAc) catalyzed synthesis of 2-aryl- and 2-heteroaryl-benzoxazoles
2
and benzothiazoles in imidazolium ionic liquids (ILs) without additives
and with recycling/reuse of the IL
⇑
Rajesh G. Kalkhambkar, Kenneth K. Laali
Department of Chemistry, University of North Florida, 1 UNF Drive, Jacksonville, FL 32224, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile, high yielding, method for the synthesis of a library of 2-aryl- and 2-heteroaryl-benzoxazoles and
Received 9 May 2012
Revised 29 May 2012
Accepted 30 May 2012
Available online 9 June 2012
benzothiazoles from readily available Schiff bases is reported employing catalytic amounts of Pd(OAc)
imidazolium ionic liquids (bmim)BF and (bmim)PF without ligands and/or additives. Simple product
isolation and recycling/re-use of the IL are additional advantages of this method.
Ó 2012 Elsevier Ltd. All rights reserved.
2
in
4
6
Keywords:
Benzoxazoles
Benzothiazoles
Synthesis from Schiff base
Pd(OAc)
Ionic liquids
2
Due to their widespread presence in biologically active natural
reported example using FeCl
catalyst.
3
Á6H
2 4
O with (bmim)BF as co-
5
e
products and pharmaceuticals benzoxazole and benzothiazole
structural motifs have received considerable attention from the
Oxidative cyclization of phenolic and thiophenolic Schiff bases
constitutes another strategy for the synthesis of substituted benz-
oxazoles and benzothizaoles. For this transformation reagents such
1
synthetic/medicinal chemistry community. Fluorinated 2-aryl-
benzothiazoles exhibit notable antitumor and metabolic activi-
2
5c
6a
6b
ties, and it has been suggested that this class of compounds are
as IBX, Pd(OAc)
2
/CsCO
3
/DMF/O
2
,
or PCC/silica/DCM have been
2
b
metabolized by cytochrome-P450 to reactive nitrenium ions.
employed. Cyclization of benzothioamides and benzothioureas
6
c
6d
6f
Apart from their importance in medicinal chemistry, the 2-aryl-
benzoxazoles and benzothiazoles have also been applied in mate-
using CuCl
2
/BINAM/base/MeCN,
2 3
Pd (dba) /monophosphine,
6
e
and DDQ/DCM, or by photolysis using chloranil in DCE/toluene,
have also been reported.
3
rials chemistry.
Transition metal-catalyzed C–H arylation of azoles constitutes a
major strategy in the synthesis of the 2-aryl derivatives. The nick-
In reviewing these literature methods and considering the re-
agents, solvents, and conditions that have been employed, it is
clear that despite reasonable diversity, development of less reagent
4
el-catalyzed reactions use ligands and additives and are performed
4
a,b
in solvents such as dioxane and DMF at high temperatures.
Pd(OAc) -catalyzed reactions also employ ligands and additives,
and are typically performed in DMF, or are used without ligands
The
2
in the presence base and various additives.4 A copper-mediated
c–f
Pd(OAc)2
XH
4
g
X
N
1
0 mol%
IL 60-75 o
-12 h
3
version with Ar-I employed CuI/PPh /base with DMF as solvent.
R
Another widely employed method for the synthesis of benzox-
azoles and benzothiazoles is via condensation of amino-phenols
and amino-thiols with aldehydes or carboxylic acids, employing
R
N
C
4
5
a
5b
PPA, or Lewis acids in solvents such as dioxane, and toluene
5c
5d
Where, R = Aryl, Heteroaryl
X = O, S
EtOAc/molecular sieves/heat, or by using KCN/DMF, with one
IL = (bmim)BF or (bmim)PF
4
6
⇑
Corresponding author. Tel.: +1 904 620 1503; fax: +1 904 620 3535.
E-mail address: kenneth.laali@UNF.edu (K.K. Laali).
Scheme 1. Pd(OAc)
and benzothiazoles.
2
-catalyzed synthesis of 2-aryl- and 2-heteroaryl-benzoxazoles
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.155

R. G. Kalkhambkar, K. K. Laali / Tetrahedron Letters 53 (2012) 4212–4215
4213
Table 1
Pd(OAc)
2
-catalyzed synthesis of 2-aryl and 2-heteroaryl-benzoxazolesa,b,c
Pd(OAc)2
0 mol%
OH
N
O
N
1
Ar
o
IL 60-75 C
-12 h
Ar
4
Entry
1a
Ar
Product
IL
Time (h)
6
Isolated yield (%)
O
(bmim)PF
6
84
80
N
O
2a
3b
4c
5a
O
(bmim)BF
(bmim)BF
(bmim)BF
(bmim)BF
8
4
4
9
O
4
4
4
N
O
77
78
80
N
O
MeO
MeO
NO
2
NO
2
N
O
4
4
N
O
O N
2
O N
2
6b
7b
8c
9a
N
(bmim)BF
5
8
85
72
70
74
N
N
O
(bmim)PF
(bmim)PF
(bmim)PF
6
6
N
O
F
F
CN
N
8
N
O
CF3
6
12
N
O
CF3
N
0b
1c
N
(bmim)PF
(bmim)PF
4
89
68
1
6
6
N
O
1
12
N
H
N
N
H
a
b
c
Fresh IL was used.
2
3
nd cycle.
rd cycle.
intensive methods that are also environmentally more acceptable
is a desirable goal.
outcomes for benzothiazoles, with the isolated yields ranging from
68% to 88%.
In continuation of our studies on electrophilic and onium ion
Typically, the recovered IL could be reused for up to 3 runs be-
fore it had to be set aside for ‘clean-up’, whereupon it could be
recycled and used again in the reaction (see Ref. 10). Reactions per-
formed in the recycled/reused IL led to slightly lower isolated
yields in some cases (see Tables 1 and 2).
Aplausiblemechanisminvolving Pd-complexationtoimine nitro-
gen followed by cyclization and elimination is outlined in Scheme 2.
In summary, the present Pd-catalyzed approach provides rapid
access to a host of 2-aryl and 2-heteroaryl-benzoxazoles and benz-
thiazoles from readily available Schiff bases, without the need for
ligands, oxidants, additives, or hazardous solvents such as DMF
and dioxane. Given the importance of functionalized 2-arylazoles
7
chemistry in ionic liquids, and in connection to recent works from
8
a
our laboratory on Pd(OAc)
and cross-coupling of polyfluoroarenes with simple aromatics
2
-catalyzed Matsuda–Heck arylation,
8
b
we wish to report a facile, high yielding, method for the synthesis
of 2-aryl- and 2-heteroaryl-benzoxazoles and benzthiazoles start-
ing from the Schiff bases, employing catalytic amounts of Pd(OAc)
in imidazolium ionic liquids (bmim)BF and (bmim)PF as solvent,
2
4
6
under very mild conditions without the need for any other additive
and with recycling and reuse of the ILs (see Scheme 1).9
,10
The results for benzoxazoles are summarized in Table 1, with
isolated yields ranging from 68% to 85%. Table 2 summarizes the

4
214
R. G. Kalkhambkar, K. K. Laali / Tetrahedron Letters 53 (2012) 4212–4215
Table 2
Pd(OAc)
2
-catalyzed synthesis of 2-aryl and 2-heteroaryl-benzothiazolesa,b,c
Pd(OAc)2
0 mol%
SH
N
S
N
1
Ar
o
IL 60-75 C
Ar
4
-12 h
Entry
1a
Ar
Product
IL
Time (h)
10
Isolated yield (%)
88
S
(bmim)PF
(bmim)PF
(bmim)PF
6
6
6
N
S
2b
3c
O
9
8
80
75
O
N
S
NO
2
NO
2
N
S
4a
5a
6b
(bmim)BF
8
8
80
70
71
4
N
S
O N
2
O N
2
N
N
(bmim)PF
6
N
S
(bmim)BF
4
12
N
S
F
F
7b
8c
CN
(bmim)PF
6
12
10
12
75
76
68
N
N
S
N
N
(bmim)BF
(bmim)BF
4
4
N
S
9a
S
N
S
a
b
c
Fresh IL was used.
2
3
nd cycle.
rd cycle.
XH
N
Pd(OAc)
2
XH
H
Ar
+
X
N
X
N
- H
Ar Pd(0)
Pd(II)-assisted
intramolecular
cyclization
β-elimination
Ar
N
Ar
Pd(II)
Pd(II)
Where, X = O, S
Ar = Aryl, Heteroaryl
Scheme 2. Plausible mechanism for Pd(OAc)
2
-catalyzed cyclization and b-elimination.
in medicinal chemistry, the present IL version offers an environ-
mentally more acceptable alternative to the existing methods.
References and notes
1.
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Acknowledgment
Research support to K.L. from the University of North Florida is
gratefully acknowledged.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.
1
55.

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6
2
5.
6.
7.
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oven-dried Schlenk tube charged with (bmim)PF
5 mL). Following efficient magnetic stirring (for 30 min) the reaction mixture
was then charged with Pd(OAc) (10 mol %). The reaction mixture was stirred
6 4
or (bmim)BF ionic liquid (4–
2
at 60–75 °C and the progress of the reaction was monitored by TLC and GC–MS.
The brown-colored reaction mass was cooled to rt and the products were
extracted with dry diethyl ether (4 times). Removal of solvent under vacuum
furnished the crude products which were chromatographed with hexane/ethyl
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2
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1
13
19
cyclized products which were characterized by NMR ( H, C, F) and by GC–
MS (see Supplementary data for characterization data). The brown colored IL
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after which it was set aside for recovery and recycling as outlined in Ref. 10.
10. Procedure for recycling of ionic liquid: The combined brown-colored ionic liquids
recovered from several set of experiments were dissolved in MeCN, and filtered
through Celite to remove insoluble black particles. After removal of solvent
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5
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