Mn(OAc)3*2H2O promoted addition of arylboronic acids to quinoxalin-2-ones

Article abstract of DOI:10.1016/j.tetlet.2017.12.085

A simple method has been developed for the synthesis of 3-aryl quinoxalin-2-one derivatives through an oxidative cross-coupling of arylboronic acids with quinoxalin-2-ones using a readily available oxidant Mn(III) acetate dihydrate. This method provides 3-aryl quinoxalin-2-one scaffolds with a broad substrate scope.

Full text of DOI:10.1016/j.tetlet.2017.12.085

Accepted Manuscript
Mn(OAc)3∗2H2O Promoted Addition of Arylboronic Acids to Quinoxalin-2-
ones
Boora Ramesh, C. Ravikumar Reddy, G. Ravi Kumar, B.V. Subba Reddy
PII:
S0040-4039(17)31629-5
https://doi.org/10.1016/j.tetlet.2017.12.085
TETL 49587
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 November 2017
29 December 2017
30 December 2017
Please cite this article as: Ramesh, B., Reddy, C.R., Kumar, G.R., Reddy, B.V.S., Mn(OAc)3∗2H2O Promoted
Addition of Arylboronic Acids to Quinoxalin-2-ones, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2017.12.085
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Graphical Abstract
Mn(OAc)3*2H2O Promoted Addition of
Arylboronic Acids to Quinoxalin-2-ones
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Boora Ramesh, C. Ravikumar Reddy, G. Ravi Kumar, B.V. Subba Reddy*

1
Tetrahedron Letters
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Mn(OAc)3*2H2O Promoted Addition of Arylboronic Acids to Quinoxalin-2-ones
Boora Ramesh, C. Ravikumar Reddy, G. Ravi Kumar, B. V. Subba Reddy*
Centre for Semiochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad –500 007, India. E-mail:basireddy@iict.res.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple method has been developed for the synthesis of 3-aryl quinoxalin-2-
one derivatives through an oxidative cross-coupling of arylboronic acids with
quinoxalin-2-ones using a readily available oxidant Mn(III) acetate dihydrate.
This method provides 3-aryl quinoxalin-2-one scaffolds with a broad substrate
scope.
Available online
Keywords:
Aryl boronic acids
2009 Elsevier Ltd. All rights reserved.
Arylation
Quinoxalin-2-ones
SET reactions
Introduction
Due to their potent biological activity, the synthesis of 3-aryl
Arylation of quinoxalin-2-ones is an alternative way for the
synthesis of biologically active 3-arylquinoxalin-2(1H)-one
derivatives. Indeed, 3-aryl quinoxalin-2(1H)-one skeleton is
often present in many biologically active compounds,1 which
are found to display a broad spectrum of pharmaceutical
activities such as anti-tryposomal,2a anti-plasmodial,2b anti-
histamine,2c anti-cancer,2d anti-viral,2e,2f antitumor and
antimicrobial2g CFTR activators2h and FXa coagulation
inhibitors (Figure 1).2i Furthermore, polymers of 3-aryl
quinoxalin-2(1H)-one derivatives are used as semiconductors
in materials science.2j
quinoxalin-2(1H)-ones is of prime importance. As a result,
various synthetic approaches have been developed for their
synthesis.3 Recently, Messaoudi et al. developed an elegant
method for the construction of 3-arylquinoxalin-2(1H)-ones
through
a
cross-coupling of arylboronic acids with
arylquinoxalin-2-ones using a Pd catalyst under an oxygen
atmosphere (Figure 2).4
Ref-4c
N
N
O
ArNHNH2
PhIO
I
Ar
Ar
N
N
N
N
N
N
ArB(OH)2
Pd(OAc)2
BF4
O
O
O
Ref-4a
Ref-4b
ArB(OH)2
Mn(OAc)3*2H2O
N
X
O
X= -NH, -NCH3, -NBn, -O
Present Work
Figure 2. Previous approaches
Figure 1. Biologically active 3-arylquinoxalin-2-ones
The construction of carbon-carbon and carbon heteroatom
bonds by Free-radical reactions has received a special

2
Tetrahedron
attraction in organic synthesis.5 On the other hand,
OH
B
arylboronic acids are versatile building blocks and found wide
applications in transition metal-catalyzed cross-coupling
reactions,6 because of the high reactivity of aryl radicals.7 By
treating arylboronic acids with manganese(III) acetate are
known to generate aryl radicals, which can undergo various
reactions to give the arylated products.8 Furthermore,
manganese(III) acetate has been considered as the most
prominent single-electron oxidant in the field of free-radical
chemistry.9 However, there are no reports on the cross
coupling of aryl boronic acids with quinoxalin-2-ones using
manganese(III) acetate.
N
N
N
N
Catalyst
Solvent
OH
+
O
O
2
3b
1
Entry
Catalyst
Temp oC
Solvent Yield (%)
CH3CN
63%
100 °C
120 °C
150 °C
120 °C
Mn(OAc)3*2H2O (3 equiv)
Mn(OAc)3*2H2O (3 equiv)
Mn(OAc)3*2H2O (3 equiv)
Mn(OAc)3*2H2O (3 equiv)
1
2
3
4
CH3CN
80%
CH3CN
72%
Dioxane
-
Results and Discussion
EDC
70%
120 °C
5
Mn(OAc)3*2H2O (3 equiv)
Inspired by single electron transfer reactions, we attempted
the cross coupling of arylboronic acids with quinoxalin-2-
ones using a readily available Mn(III) acetate dihydrate as an
oxidant to produce 3-aryl quinoxalin-2-ones. The precursors
were prepared using a known procedure.10 Initially, we
performed the C-3 arylation of quinoxalin-2-one (1.1 equiv)
with phenyl boronic acid (2, 1.2 equiv) using
Mn(OAc)3*2H2O (3 equiv) as an oxidant at 100 oC in CH3CN
for 12h. The desired product 3a was obtained only in 63%
yield (Table 1, entry 1). To improve the yield, the next
Toluene
50%
120 °C
120 °C
6
Mn(OAc)3*2H2O (3 equiv)
K2S2O8 (3 equiv)
CH3CN
-
7
H2O
-
AgNO3 (0.2 equiv) K2S2O8(3 equiv)
DDQ (3 equiv)
8
25 °C
120 °C
120 °C
CH3CN
-
9
CH3CN
-
CAN (3 equiv)
10
aQuinoxalinone (0.625 mmol), boronic acid (0.745 mmol), Mn(OAc)3*2H2O
(1.87) in CH3CN (2 mL) under argon for 12h in a seal tube.
o
reaction was carried out at 120 C. To our delight, the desired
product was obtained in 80% yield (Table 1, entry 2). By
further increasing the temperature to 150 C, the yield was
o
The scope of this method is exemplified with wide range of
arylboronic acids with NH-, N-methyl- and N-benzyl-
quinoxalin-2-ones and the results are presented in Table 2.
The substituents that are present on nitrogen atom of the
dropped down to 72% (Table 1, entry 3). Therefore, the
optimum temperature was 120 oC to achieve the best
conversion. Next we examined the effect of solvents such as
1,4-dioxane, EDC, and toluene at 120 oC. The reaction didn’t
proceed in 1,4-dioxane (Table 1, entry 4). However, the
product was obtained only in 70% yield in EDC (Table 1,
entry 5) and 50% in toluene (Table 1, entry 6). The reaction
was further tested using other oxidants such as K2S2O8, DDQ
and CAN. Accordingly, we performed the reaction using
K2S2O8 (3 equiv) in CH3CN at 120 oC.11 But no desired
product was formed even by adding additive (AgNO3) or
changing the solvent to H2O (Table 1, entries 7,8). Similarly,
DDQ and CAN in acetonitrile under reflux conditions failed
to give the desired product (Table 1, entries 9,10).
quinoxalin-2(H)-one ring did not show a considerable effect
on conversion. However, quinoxalin-2(1H)-one with free NH
group gave the product in lower yield when compared to N-
methyl quinoxalin-2(1H)-one. This is due to the reaction
between Mn(OAc)3.2H2O and free NH group. Furthermore,
the substituent present on arylboronic acid had shown some
effect on the conversion. Aryl boronic acids having electron
donating group at para position afforded the product in high
yield (Table 2, 3m) compared to electron deficient substrate
i.e. (4-nitrophenyl)boronic acid (Table 2, 3g). This is
attributed to the presence of electron donating group at para
position stabilizes the aryl radical and provides the product
slightly in higher yield when compared to electron deficient
substituent. Furthermore, the electron-rich meta-substituted
arylboronic acid, for instance, (3-methoxyphenyl)boronic acid
gave the arylated product slightly in higher yield (Table 2, 3j)
compared to (3-nitrophenyl)boronic acid (Table 2, 3i). The
reaction was also successful with 2H-benzo[b][1,4]oxazin-2-
one (Table 2, 3o). The corresponding 3-phenyl-2H-
benzo[b][1,4]oxazin-2-one was obtained in 60% yield.
However, both furan-2-ylboronic acid and thiophen-3-
ylboronic acid failed to give the desired products under
present conditions.
Table 1. Optimization of reaction conditions

3
Table 2. Addition of arylboronic acids on cyclic imines
Scheme 1. A plausible reaction mechanism
N
Ar
O
N
X
Mn(OAc)3*2H2O
OH
B
For further transformation of products, we attempted the C-H
amidation of 3b13 at ortho position of aryl ring with tosyl
azide (4, 1.5 equiv) using Cu(OAc)2 (2 equiv), AgSbF6 (20
mol%) in the presence of dichloro(p-cymene)ruthenium(II)
dimer (5 mol%). The reaction was complete in 12h at 120 oC
in EDC affording the desired product 5 in 60% yield (Scheme
2).
+
CH3CN,120 oC,12h
Ar
OH
X
3
Ar = aryl
O
2
1
X= -NH, -NCH3, -NBn, -O
CH3
N
N
N
N
N
O
N
H
O
O
Cu(OAc)2(2 equiv)
O
N3
3c
3b
88%
3a
80%
70%
N
N
S
Ru(p-cymene)Cl2 (5 mol%)
O
O
+
H3C
(20 mol%), DCE,
AgSbF6
O
O
O
120 oC, 12h
N
N
N
N
N
3b
4
TsHN
O
O
N
O
N
N
3f
3e
3d
82%
80%
75%
CF3
NO2
O
5
N
N
N
N
N
NO2
Scheme 2. ortho-Amidation of 3-aryl quinoxalin-2(1H)-one
N
O
O
O
3i
77%
3g
3h
79%
76%
Conclusions
Cl
N
N
N
OCH3
OCH3
Cl
In summary, we have developed a simple and convenient
method for the synthesis of 3-aryl quinoxalin-2-ones using
Mn(OAc)3*2H2O as an effective oxidant. This method is an
useful alternate to previously reported precious metal
N
O
N
O
N
O
3l
80%
3k
3j
83%
82%
catalyzed approaches.
N
N
N
General procedure
N
O
N
O
O
O
3n
3o
82%
60%
3m
85%
A sealed tube was charged with quinoxalin-2(1H)-one (1,
0.625 mmol) and CH3CN (5 mL) and the solution was purged
with argon gas for 30 min and then Mn(OAc)3*2H2O (1.873
mmol) and arylboronic acid (2, 0.745 mmol) were added.
After removal of oxygen by argon gas, the reaction vessel was
sealed with a Teflon screw. The reaction was stirred at 120 °C
for 12h. The resulting suspension was cooled to room
temperature and diluted with ethyl acetate. The organic layer
was filtered through Whatman filter paper and evaporated
under reduced pressure. The residue was purified by flash
chromatography over silica gel to afford the desired product.
aAll products were characterized by NMR, IR and mass spectrometry.
bYield refers to pure products after chromatography.
Based on previous reports,12 we proposed a plausible reaction
path way as shown in Scheme 1. The reaction proceeds
through the formation of an aryl radical A from arylboronic
acid in the presence of Mn(OAc)3*2H2O. A subsequent
addition of aryl radical A onto -CH=N- would give the
nitrogen radical B. Further generation of another radical by
Mn(OAc)3*2H2O afforded the desired product (3). Though
the reaction proceeds with 2 equiv of Mn(OAc)3*2H2O, the
reaction took a long reaction time to achieve good conversion.
ortho-C-H amidation of 1-methyl-3-phenylquinoxalin-
2(1H)-one
A mixture of 1-methyl-3-phenylquinoxalin-2(1H)-one (3b, 1
mmol), sulfonyl azide (4, 1.5 mmol), [RuCl2(p-cymene)]2 (5
mol%), Cu(OAc)2 (2 equiv) and AgSbF6 (20 mol%) in
o
dichloroethane (5.0 mL) was stirred at 120 C over 12h in
sealed tube. Up on completion, as monitored by TLC, the
mixture was diluted with dichloromethane and passed through
a small pad of Celite. After removal of the solvent, the crude
mixture was purified by column chromatography using silica
gel to afford the pure product 5

4
Tetrahedron
Acknowledgements
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Supplementary Information
Characterization data and copies of 1H & 13C NMR spectra of
products (3a-o and 5) are provided in SI.
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6
Tetrahedron
Highlights
This is the first report using Mn(OAc)3
•
•
Describes the addition of aryl boronic acids
to cyclic imines
•
•
•
This method is cost effective and
operationally simple
It is compatible with various functional
groups
This method works with a diverse range of
substrates