Palladium-catalyzed direct arylation of pyridine N-oxide with 2-bromoacetanilides. Synthesis of benzisoxazolo[2,3-a]pyridinium tetrafluoroborates

Article abstract of DOI:10.1016/j.tetlet.2011.11.110

The synthesis of a variety of novel benzisoxazolo[2,3-a]pyridinium tetrafluoroborates is described. These compounds are conveniently prepared from pyridine N-oxide via a microwave-promoted palladium-catalyzed direct arylation of pyridine N-oxide with 2-bromoacetanilides to give 2-(2-acetamidoaryl)pyridine N-oxides, followed by hydrolysis, diazotization, and intramolecular displacement of nitrogen which affords the target benzisoxazolo[2,3-a]pyridinium tetrafluoroborates.

Full text of DOI:10.1016/j.tetlet.2011.11.110

Tetrahedron Letters 53 (2012) 612–615
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Tetrahedron Letters
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Palladium-catalyzed direct arylation of pyridine N-oxide with
2-bromoacetanilides. Synthesis of benzisoxazolo[2,3-a]pyridinium
tetrafluoroborates
⇑
Jeffery T. Myers, James M. Hanna Jr.
Department of Chemistry, Physics, and Geology, Winthrop University, 313B Sims Science Building, Rock Hill, SC 29733, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a variety of novel benzisoxazolo[2,3-a]pyridinium tetrafluoroborates is described. These
compounds are conveniently prepared from pyridine N-oxide via a microwave-promoted palladium-
catalyzed direct arylation of pyridine N-oxide with 2-bromoacetanilides to give 2-(2-acetamidoaryl)pyr-
idine N-oxides, followed by hydrolysis, diazotization, and intramolecular displacement of nitrogen which
affords the target benzisoxazolo[2,3-a]pyridinium tetrafluoroborates.
Received 18 October 2011
Revised 18 November 2011
Accepted 22 November 2011
Available online 28 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Benzisoxazolo[2,3-a]pyridinium
Palladium-catalyzed direct arylation
Pyridine N-oxide
Microwave synthesis
Introduction
desired compound 1, therefore we sought to synthesize several dif-
ferently substituted 2-(2-aminoaryl)pyridine N-oxides, from which
The benzo[4,5]furopyridine substructure (Fig. 1) is a common
motif in a variety of biologically active compounds. Substances
containing this structural unit have been shown to exhibit activity
against cancer,1,2 tuberculosis,3 osteoporosis,4 and HIV.5
Although considerable effort has been directed toward the syn-
thesis of these compounds,6–8 the related ring system benzisoxazol-
o[2,3-a]pyridinium (1, Fig. 2) has not attracted as much attention;
in fact only two examples have been reported to date.9
Abramovitch and Inbasekaran described the synthesis of 1
(R = H) from 2-(2-aminophenyl)pyridine N-oxide by conversion to
the diazonium salt followed by intramolecular displacement of
nitrogen in refluxing acetonitrile (Scheme 1); this compound was
then nitrated to give 1 (R = NO2). A related benzisoxazolo[2,3-b]iso-
quinolinium tetrafluoroborate was prepared by Timári et al. in a
similar manner.10 Given the biological activity of the benzo[4,5]
furopyridines and that the similar 2-arylisoxazolo[2,3-a]pyridini-
um salts11 have been reported to be useful for the treatment of
inflammation and gastric hyperacidity,12 we became interested in
developing a general synthesis of compounds of type 1 to facilitate
any future investigations of their pharmacological properties.
We felt that the Abramovitch strategy (Scheme 1) involving ring
closure of a diazonium salt derived from an appropriate 2-
(2-aminoaryl)pyridine N-oxide was the simplest approach to the
we could carry out the diazotization and attempt ring closure to 1. A
search of the literature uncovered very few approaches to the
required 2-(2-aminoaryl)pyridine N-oxides; most resulted from
oxidation of the corresponding 2-(2-aminoaryl)pyridine.13 These
compounds were prepared either by reduction of the corresponding
2-(2-nitroaryl)pyridine (prepared by reaction of pyridine with an
o-nitroaryldiazonium salt14,15), by palladium-catalyzed cross-cou-
pling of a (2-aminophenyl)boronate ester with a 2-halopyridine,16
or by palladium-catalyzed coupling of 2-pyridylzinc bromide with
2-haloaniline.17 Since many of these existing methods suffer from
low yields or limited scope, we decided to explore the palladium-
catalyzed direct arylation of pyridine N-oxide (2) with an appropri-
ate 2-bromoacetanilide (3) using the method developed by
Fagnou.18,19 Although this protocol had not yet been applied using
2-bromoacetanilides as coupling partners, we believed it would
provide a simple route to a wide variety of acetylated 2-(2-amino-
aryl)pyridine N-oxides (4). Subsequent hydrolysis, diazotization to
5 and ring closure would then afford 1 (Scheme 2).
N
N
O
O
O
O
N
N
⇑
Corresponding author. Tel.: +1 803 323 4933; fax: +1 803 323 2246.
E-mail address: hannaj@winthrop.edu (J.M. Hanna Jr).
Figure 1. Benzo[4,5]furopyridines.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.110

J. T. Myers, J. M. Hanna Jr. / Tetrahedron Letters 53 (2012) 612–615
613
BF4
N
O
R
1
(R = H, NO2)
Figure 2. Benzisoxazolo[2,3-a]pyridinium tetrafluoroborates.
Pd(OAc)2 (5 mol%)
Ligand (15 mol%)
K2CO3
NHAc
NHAc
NH2
N2BF4
BF4
Br
1. NaNO2, HCl
2. NaBF4
Δ
N
O
+
N
O
N
O
N
O
N
O
CH3CN
PhMe, 140 °C, μWave
2
3a
4a
Scheme 1. Abramovitch synthesis of 1.9
Ligand
(NMR)
% Yield
tBu3P-HBF4
tBu2MeP-HBF4
Cy3P-HBF4
H2IPr-HBF4
53
We can now report that the pathway described in Scheme 2 is a
viable route to a variety of benzisoxazolo[2,3-a]pyridinium tetra-
fluoroborates (1). In this Letter, we describe the results of our study.
80
23
35
Results and discussion
Scheme 3. Direct arylation of 2 with 3a.
We began our study by examining the direct arylation of pyri-
dine N-oxide (2) with 20-bromo-40-methylacetanilide (3a). Initially,
we found that microwave heating of a mixture of 2 (4 equiv) with
3a in the presence of palladium acetate (5 mol %), tri-tert-butyl-
phosphonium tetrafluoroborate (15 mol %), and potassium carbon-
ate (2 equiv) in toluene to 140 °C using no special oxygen- or
water-exclusion techniques gave compound 4a in a 35% yield after
chromatography (average of 3 runs).20 The balance was mainly 40-
methylacetanilide, resulting from protiodebromination of 3a, plus
a small amount (ꢀ5%) of 3a. Screening of various ligands using
yields determined by 1H NMR revealed that di-tert-butylmethyl-
phosphonium tetrafluoroborate gave the best results among the li-
gands studied (80% yield, Scheme 3), therefore it was used for all
further direct arylations. The other phosphonium salts as well as
the N-heterocyclic carbene precursor 1,3-bis(2,6-di-isopropylphe-
nyl)-4,5-dihydroimidazolium tetrafluoroborate (H2IPr-HBF4) were
not as effective. Under these conditions, 4a was produced in an
average yield of 65% after chromatographic purification.
We were able to prepare several examples of 4 containing both
electron-withdrawing and electron-donating substituents using
this protocol; the results are shown in Table 1. Small-scale runs
(0.6 mmol 3) were performed using a 10-mL vessel and were usu-
ally completed within 1 h, while larger scale runs (3.0 mmol 3),
carried out in an 80-mL vessel, generally required about 3 h for
complete reaction. The direct arylation proceeded smoothly in
most cases to give synthetically useful yields of 4; the exception in-
volved the reaction of 20-bromo-40-chloroacetanilide (3h, entry 8),
which gave virtually no 4h under the standard conditions. Fortu-
nately, lowering the reaction temperature from 140 °C to 110 °C al-
lowed us to overcome this limitation and as a result, 4h could be
synthesized in a 51% yield. We speculate that side reactions involv-
ing oxidative addition to the carbon–chlorine bond to the palla-
dium catalyst were occurring at 140 °C, and that these were
minimized at the lower temperature.
The observation that the direct arylation of 3h could occur at
the lower temperature (i.e., at the boiling point of the solvent tol-
uene) suggested the possibility that the reaction may give an
acceptable yield in a reasonable amount of time under standard re-
flux conditions without requiring microwave heating. We there-
fore conducted direct arylations of both 3a and 3h in refluxing
toluene using conventional (oil-bath) heating and determined the
product yields by 1H NMR. Under these conditions, 4a was pro-
duced in a 62% yield from 3a after a 3 h reflux period. No unreacted
3a was detected; the remainder was 40-methylacetanilide (debro-
minated 3a). Although this is a reasonable yield, it is lower than
the 80% yield we found during our ligand screening experiments
(Scheme 3). Under similar conditions, however, 3h gave only a
20% yield of 4h. In this case, some unreacted 3h was detected
but the major product appeared to be the debrominated starting
material 40-chloroacetanilide. Based on these results, it seems that
microwave heating is necessary to consistently achieve the prod-
uct yields reported in Table 1.21
Having a method to prepare the required starting material for
the cyclization in hand, we turned our attention to the hydrolysis,
diazotization, and cyclization. Initial experiments employing 4a
indicated that both the hydrolysis (in refluxing aqueous HCl) and
diazotization (NaNO2/HCl) proceeded smoothly as expected, but
in our hands isolation of the diazonium salt by precipitation as
the solid tetrafluoroborate salt proved difficult. This problem was
solved by hydrolyzing 4a in aqueous HBF4 to the anilinium tetra-
fluoroborate which, after removal of the water and replacement
with acetonitrile, could be diazotized with tert-butyl nitrite. Cycli-
zation to compound 1a occurred smoothly in the same solution by
heating it to reflux for a short period of time. Using this protocol,
hydrolysis, diazotization, and cyclization of 4 proceeded efficiently
in all cases. The results are shown in Table 2.
NHAc
NHAc
R
N2BF4
BF4
[Pd]
Br
1. Hydrolysis
2. Diazotization
N
O
N
O
N
O
+
N
O
R
R
R
2
3
4
5
1
Scheme 2. Proposed general route to 1.

614
J. T. Myers, J. M. Hanna Jr. / Tetrahedron Letters 53 (2012) 612–615
Table 1
Preparation of 4a
Pd(OAc)2 (5 mol%)
NHAc
NHAc
R
tBu2MeP-HBF4(15 mol%)
Br
N
O
+
N
O
K2CO3 (2 equiv)
PhMe, 140 °C, μWave
R
2
3
4
Entry
1
Acetanilide (3)
NHAc
Product (4)
NHAc
N
O
Yieldb (%)
Entry
5
Acetanilide (3)
Product (4)
NHAc
Yieldb (%)
NHAc
Br
Br
N
O
65
60
F
F
3e
4e
3a
NHAc
4a
NHAc
NHAc
Br
NHAc
Br
N
O
N
O
2
3
4
65
76
55
6
70
64
51
3b
NHAc
OCF3
3f
4b
NHAc
OCF3
4f
NHAc
NHAc
Br
Br
Br
N
O
N
O
7
3c
4c
NHAc
OCH3
3g
OCH3
4g
NHAc
NHAc
NHAc
Br
N
O
N
O
8c
F
Cl
F
Cl
3d
4d
3h
4h
a
Experiments carried out with 2 (4 equiv), 3 (1 equiv), Pd(OAc)2 (5 mol %), tBu2MePꢁHBF4 (15 mol %), K2CO3 (2 equiv) in toluene (3.3 mL/mmol
3). The mixture was heated to 140 °C in a CEM/Discover Benchmate microwave reactor.
b
Isolated yields; average of at least 2 runs.
Heated to 110 °C.
c
Table 2
Preparation of benzisoxazolo[2,3-a]pyridinium tetrafluoroborates (1)a
NHAc
BF4
1. HBF4, H2O, reflux
N
N
O
2. tBuONO, CH3CN, reflux
O
R
R
4
1
Entry
1
Acetanilide (4)
Product (1)
Yieldb (%)
Entry
5
Acetanilide (4)
Product (1)
Yieldb (%)
BF4
N
O
BF4
N
O
4a
72
4e
80
F
1a
1e
BF4
N
O
BF4
N
O
OCF3
2
4b
77
6
4f
71
1f
1b
BF4
N
BF4
N
O
3
4
4c
83
79
7
8
4g
4h
76
74
OCH3
Cl
O
1c
1g
BF4
N
O
BF4
N
O
4d
F
1d
1h
a
Hydrolysis: 4 (1.0 mmol), HBF4 (50% aqueous solution, 1.2 mmol), water (1 mL), were refluxed until hydrolysis was complete. Diazotization/
cyclization: the preceding mixture was evaporated in vacuo and dissolved in CH3CN (8 mL). tBuONO (1.2 mmol) was added. Mixture was stirred
1 h at rt, then heated to reflux.
b
Isolated yields; average of at least 2 runs.

J. T. Myers, J. M. Hanna Jr. / Tetrahedron Letters 53 (2012) 612–615
615
Summary
In summary, we have shown that a variety of novel benzisoxaz-
olo[2,3-a]pyridinium tetrafluoroborates (1) can be conveniently
prepared from pyridine N-oxide, which may facilitate investiga-
tions into the biological activity of these compounds. In doing so,
we have also expanded the scope of the palladium-catalyzed direct
arylation of pyridine N-oxide to include 2-bromoacetanilides as
coupling partners to give the previously unknown 2-(2-acetamido-
aryl)pyridine N-oxides (4). In addition, we have shown that the di-
References and notes
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20. To our knowledge, this is the first example of the application of microwave
heating to the direct arylation of pyridine N-oxide, although Kappe et al. have
recently reported the microwave-promoted direct arylation of electron-rich
heterocycles with aryl and heteroaryl halides 20 Baghbanzadeh, M.; Pilger, C.;
Kappe, C. O. J. Org. Chem. 2011, 76, 8138.
rect arylation gives
4 in synthetically useful yields using
microwave heating without any special water- or oxygen-exclu-
sion techniques. Further application of this strategy to the synthe-
sis of other novel heterocyclic systems is being investigated in our
laboratory.
Acknowledgments
The project described was supported by NIH Grant Number P20
RR-016461 from the National Center for Research Resources. Addi-
tional support was provided by the Winthrop University Depart-
ment of Chemistry, Physics, and Geology and the Winthrop
University Research Council.
Supplementary data
Supplementary data (experimental procedures, detailed prod-
uct characterization data, compound spectra) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.11.110.
21. Although the reasons for this are unclear, microwave heating has been
reported to give better yields, reduce side reactions and improve
reproducibility in certain cases. For a review see 21 Kappe, C. O. Angew.
Chem., Int. Ed. 2004, 43, 6250.