AgNO2-mediated direct nitration of the quinoxaline tertiary benzylic C-H bond and direct conversion of 2-methyl quinoxalines into related nitriles

Article abstract of DOI:10.1039/c4cc01327a

A unique method for AgNO₂-mediated direct nitration of the quinoxaline tertiary C-H bond and direct conversion of 2-methyl quinoxalines into 2-quinoxaline nitriles under oxidative conditions has been developed. This protocol provides an efficient way to access quinoxaline containing nitroalkanes and nitriles depending on different substrate selection. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01327a

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AgNO2-mediated direct nitration of the
quinoxaline tertiary benzylic C–H bond and
direct conversion of 2-methyl quinoxalines into
related nitriles†
Cite this: Chem. Commun., 2014,
50, 10857
Received 20th February 2014,
Accepted 21st July 2014
Degui Wu, Jian Zhang, Jianhai Cui, Wei Zhang and Yunkui Liu*
DOI: 10.1039/c4cc01327a
www.rsc.org/chemcomm
A unique method for AgNO2-mediated direct nitration of the quinoxaline coupling partners, and the generation of a large amount of organic
tertiary C–H bond and direct conversion of 2-methyl quinoxalines into or inorganic wastes. Owing to the abundance of methyl arenes, the
2-quinoxaline nitriles under oxidative conditions has been developed. direct conversion of methyl arenes into the related aromatic nitriles
This protocol provides an efficient way to access quinoxaline containing has become an important and practical route to access aryl
nitroalkanes and nitriles depending on different substrate selection.
nitriles.14 However, such a procedure using NH3 as the N-source
for the formation of the cyano group usually requires very high
Nitro compounds are widely used in the chemical industry as well temperature (4350 1C). Recently, Jiao15 and Wang16 reported two
as in the academic research.1–3 In contrast to the easy nitration mild methods for the conversion of methyl arenes into aryl nitriles
of aromatic C–H bonds by nitrating agents, the selective nitration by using NaN3 and tert-butyl nitrite (tBuONO), respectively, as the
of aliphatic C–H bonds is very difficult. The nitration process of N-source for the formation of the cyano group. Overall, the
aliphatic hydrocarbons usually requires high temperatures synthetic methods involving the direct transformation of methyl
(4200 1C) which will cause undesired C–C bond scissions, thus arenes into aryl nitriles remain largely under-explored. As part of
leading to poor selectivities and adding difficulties for the product our continued interest in the transition metal-involved sp3 C–H
separation.4 As a consequence, the preparation of nitroalkanes bond functionalizations,17–19 we herein present a unique AgNO2-
generally relies on methods other than the direct C–H nitration.5 In mediated direct nitration of the quinoxaline tertiary C–H bond and
last decades, despite several more mild processes for the nitration direct conversion of 2-methyl quinoxalines into 2-quinoxaline
of aliphatic hydrocarbons being reported,6 selectivity has remained nitriles in the presence of K2S2O8.
a big problem. Therefore, it is still desirable to develop methods for
highly selective nitration of aliphatic C–H bonds.
The present finding originated from our recent study on the
regiospecific preparation of nitroarenes via palladium-catalyzed
On the other hand, aryl nitrile compounds as versatile chelation-assisted nitration of aromatic C–H bonds.20 When
synthetic intermediates are widely used in the synthesis of 2-isopropylquinoxaline 1a was subjected to the same reaction
natural products, functional materials, medicines, agricultural conditions (10 mol% Pd(OAc)2, 2.0 equiv. AgNO2 and K2S2O8,
chemicals, and dyes.7 Besides, they also serve as important 130 1C, 48 h) for the ortho-nitration of 2-arylquinoxalines
precursors for the preparation of a variety of molecules including described in our previous work20 (entry 1, Table 1), we expected
acids, aldehydes, amines, amides, and N-containing heterocycles.8 that the methyl C–H bond in 1a could also be nitrated to yield
Some representative methods for the synthesis of aryl nitriles 3a. It was found that no target product 3a was formed while a
include the Sandmeyer reaction,9 the Rosenmund–von Braun benzylic C–H bond nitrated product 2a was unexpectedly
reaction,10 transition-metal-catalyzed cross-coupling reactions of obtained in 63% yield (entry 1). Control experiments showed
aryl halides with metallic11 or nonmetallic cyano-group sources,12 that in the absence of Pd(OAc)2 or K2S2O8, 2a was produced in
and the dehydration of primary aromatic amides.13 However, most 64% and 5% yields, respectively (entries 2 & 3), indicating that
of these methods suffer from one or more limitations with respect Pd(OAc)2 did not participate in the nitration process while
to the use of toxic reagents, the need for prefunctionalization of K2S2O8 was indispensable. Further experiments disclosed that
110 1C was a more suitable temperature for getting a good yield
State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology,
of 2a (entry 4 vs. 2). Note that using 1.2 equivalents of AgNO2
and K2S2O8 was enough for the reaction to be completed (entry 5).
Among several solvents (entries 5–15) and oxidants (entries 5 and
Zhejiang University of Technology, Hangzhou 310014, P. R. China.
E-mail: ykuiliu@zjut.edu.cn; Fax: +86 571 8832 0066; Tel: +86 571 88871534
† Electronic supplementary information (ESI) available: Detailed experimental
16–22) examined, it was proven that DCE was the best choice of
solvent and K2S2O8 was the best choice of oxidant. Attempting to
procedure, charts of the mechanistic studies, and analytical data for all products.
See DOI: 10.1039/c4cc01327a
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Table 1 Optimization of reaction conditionsa
Table 2 AgNO2-mediated nitration of the quinoxaline benzylic C–H
bonda
Entry
R1
R2, R3
R4 (1)
Product (2)
Yieldb (%)
1
2
3
4
5
6
7
8
H
H
H
H
H, H
H (1a)
H (1b)
H (1c)
H (1d)
H (1e)
H (1f)
H (1g)
H (1h)
H (1i)
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
82 (71c )
64
61
77
75
Me, Me
Cl, Cl
NO2, H
Br, H
Entry Nitro source
Oxidant Add.
Solvent Yield of 2a b (%)
63e
c
c
d
1
2
3
4
5
6
7
8
AgNO2 c
AgNO2 c
AgNO2 c
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
KNO2
K2S2O8 c Pd(OAc)2 DCE
H
K2S2O8
—
—
—
DCE
DCE
DCE
DCE
64e
Me
Me
Me
Me
Me
Me
H
H
H
H
H, H
55d,e
77d,e
74d,e
80d,e
87d,e
82d,e
62d,e
45d,e, f
45d,e, f
43d,e, f
5e
Me, Me
Cl, Cl
NO2, H
Br, H
Cl, H
H, H
Me, Me
Cl, Cl
Cl, H
c
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
75, 68 f
82
9
CH2Cl2 78
Toluene 16
MeCN 70
DMF
Et2O
THF
Acetone 27
HOAc 61
EtOAc Trace
MeNO2 77
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
10
11
12
13
14
15
H (1j)
H (1k)
Ph (1l)
Ph (1m)
Ph (1n)
Ph (1o)
9
53
16
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
16
Traceg
Cu(OAc)2
CuCl2
PhI(OAc)2
DDQ
Trace
10
12
Trace
16
41
6
18
50
0
CAN
tBuOOBut
TBHP
17
K2S2O8
AgNO2 g/KNO2 K2S2O8
h
70 (69h)
a
Reaction conditions: 1a (0.15 mmol), AgNO2 (1.2 equiv.), oxidant (1.2 equiv.),
solvent (1.5 mL), 110 1C for 48 h unless otherwise noted. b Isolated yield.
c The amount is 2.0 equiv. d The amount is 10 mol% of 1a. e The reaction
was conducted at 130 1C. f The reaction was conducted at 100 1C. g The
amount is 0.2 equiv. h The amount is 1.2 equiv.
0
use the cheap KNO2 as the nitro source resulted in a low yield of
2a (18%, entry 23). However, a combination of 0.2 equiv. AgNO2
with 1.2 equiv. KNO2 as the nitro source could give an acceptable
yield of 2a (50%, entry 24).
18
19
60
With the optimized reaction conditions in hand, we set out to
investigate the scope of substrates (Table 2). For substrates
possessing a tertiary benzylic carbon, the corresponding benzylic
C–H bond could be successfully nitrated to afford nitroalkane 2
in moderate to good yields (2a–2o). Unfortunately, the benzylic
C–H bond in 2-cyclopropylquinoxaline 1p failed to be nitrated
and the starting material was recovered. When a substrate 1q
bearing a secondary benzylic carbon was used, the reaction
failed to give the corresponding nitrated product while the
benzylic C–H bond ketonized product 2q0 was obtained in 70%
yield. An attempt to conduct the reaction of 1q in a degassed
solvent under an argon atmosphere still gave 2q0 in similar yield
whereas no formation of 2q was detected. Note that 1 substituted
0g
0g
20
a
Reaction conditions: 1 (0.3 mmol), AgNO2 (1.2 equiv.), K2S2O8 (1.2 equiv.),
DCE (1.5 mL), 110 1C for 48 h unless otherwise noted. b Isolated yield.
c The reaction was performed on a 1 mmol scale. d The reaction was
conducted at 130 1C. e The reaction time is 72 h. f The use of 1.8 equiv. of
AgNO2 and K2S2O8, respectively. g The starting material was recovered. h The
reaction was carried out in a degassed solvent under an Ar atmosphere.
To further expand the scope of the present reaction, the
with a phenyl group at the 3-position resulted in decreased yields nitration of the quinoxaline primary benzylic C–H bond was
of 2 compared with those without a substituent due to the low also carried out. When 2-methyl-3-phenylquinoxaline 8a was
conversion of the starting substrates (2l–2o vs. 2a–2e). When 1r treated with 1.4 equiv. of AgNO2 and K2S2O8 in DCE at 130 1C
having a gem-diphenyl substituted benzylic C–H bond was used, for 72 h, to our surprise, a 2-quinoxalinyl nitrile 9a, rather than
the reaction gave a hydroxylated product 2r0 in 60% yield while a nitrated product, was unexpectedly isolated in 43% yield
no formation of 2r was detected. The nitration of the tertiary (entry 1, Table 3). The yield of 9a could be increased to 82%
benzylic C–H bond of N-containing heterocycles 4 and 6 was not by using 2.2 equiv. of AgNO2 and K2S2O8, respectively (entry 1,
successful under the present reaction conditions while the Table 3). Preliminary studies showed that a number of 2-methyl
starting substrate was recovered.
quinoxalines could be converted into the corresponding
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Table 3 AgNO2-mediated direct conversion of 2-methyl quinoxalines to
the corresponding aromatic nitrilesa
Scheme 2 Proposed mechanism for the formation of 9a and 2q0.
Entry
R1
R2
Sub. (8)
Prod. (9)
Yieldb (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
Me
H
8a
8b
8c
8d
8e
8f
9a
9b
9c
9d
9e
9f
43c, 82
65
80
75
78
70
64
68
2-OMe
3-OMe
4-Me
4-F
4-Cl
4-Br
H
and oxime intermediates (14 and 15).16 Under the oxidative
conditions, ketoxime 14 and aldoxime 15 could be further
converted into ketone 2q0 and nitrile 9a, respectively.16
In summary, we have developed a novel method for the
AgNO2-mediated direct nitration of the quinoxaline tertiary
C–H bond and direct conversion of 2-methyl quinoxalines into
2-quinoxaline nitriles in the presence of K2S2O8, which represents
the first example of transition metal-involved sp3 C–H nitrations17,18
and silver-mediated direct conversion of the benzylic methyl group
into a cyano group with the use of NO2ꢀ as the N-source.14–16 Further
exploration of this new approach for the synthesis of more valuable
compounds is underway in our laboratory.
8g
8h
9g
9h
a
Reaction conditions: 8 (0.3 mmol), AgNO2 (2.2 equiv.), K2S2O8
(2.2 equiv.), DCE (4.0 mL), 130 1C under an argon atmosphere for
b
c
72 h unless otherwise noted. Isolated yield. The amount of AgNO2
and K2S2O8 is 1.4 equiv., respectively.
aromatic nitriles in moderate to good yields (9a–9h, 60–82%,
Table 3).
To gain insight into the mechanism of the benzylic C–H
nitration process, a mixture of substrates 1a and [D]-1a was
subjected to determine the intermolecular isotope effect (see
the ESI†). A secondary kinetic isotope effect as showing kH/kD E
1.1 was observed, suggesting that the reaction might involve a
radical process.5a,b When the reaction was conducted in the
presence of TEMPO, a radical scavenger,21 the benzylic C–H
nitration was suppressed (see the ESI†), thus further supporting
a radical process.20
On the basis of the above experiments and previous litera-
tures,19b,20,22,23 a proposed mechanism for the AgNO2-mediated
nitration of the quinoxaline benzylic C–H bond is described in
Scheme 1. On the one hand, AgNO2 may release the NO2 radical
upon treatment with20,22a or without K2S2O8.22b,c Over the
course of the reaction, the formation and gradual consumption
of a brown gas, which should be assigned to NO2 gas,20,22 were
indeed observed in the sealed tube. On the other hand, Ag(I)
could be oxidized into Ag(II) species which then underwent
single electron transfer from 1a to generate a radical inter-
mediate B (or C).19b,23 The combination of the radical species
NO2 and B finally gave nitroalkane 2a.
We are grateful to the Natural Science Foundation of China
(No. 21172197 and 21372201), Zhejiang Province (Grant No.
Y407168), and the Opening Foundation of Zhejiang Key Course
of Chemical Engineering and Technology, Zhejiang University
of Technology for financial support.
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direct conversion of 8a to 9a is proposed in Scheme 2. These
two processes might involve the formation of an NO radical24
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Scheme 1 Proposed mechanism for the nitration of 1a.
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10860 | Chem. Commun., 2014, 50, 10857--10860
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