Arylnitration of alkenes by nitration/C-H functionalization cascade using AgNO3 and HOAc

Article abstract of DOI:10.1016/j.tetlet.2014.02.043

A novel arylnitration of alkenes by nitration and C-H functionalization cascade process has been developed. This methodology provides an efficient way to construct a variety of nitro-containing oxindoles and dihydroquinolin-2(1H)-ones. In addition, the process exhibits significant functional group tolerance. Moreover, the use of inexpensive and readily available starting materials makes this practical and atom-economical approach particularly attractive.

Full text of DOI:10.1016/j.tetlet.2014.02.043

Tetrahedron Letters 55 (2014) 2119–2122
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Tetrahedron Letters
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Arylnitration of alkenes by nitration/C–H functionalization cascade
using AgNO3 and HOAc
a
a
b
Ya-Min Li a, , Yuehai Shen , Kwen-Jen Chang , Shang-Dong Yang
⇑
a Faculty of Life Science and Technology, Kunming University of Science and Technology, 727 Jingming Nanlu, Kunming 650500, China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Nanlu, Lanzhou 730000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel arylnitration of alkenes by nitration and C–H functionalization cascade process has been devel-
oped. This methodology provides an efficient way to construct a variety of nitro-containing oxindoles and
dihydroquinolin-2(1H)-ones. In addition, the process exhibits significant functional group tolerance.
Moreover, the use of inexpensive and readily available starting materials makes this practical and
atom-economical approach particularly attractive.
Received 24 December 2013
Revised 21 January 2014
Accepted 13 February 2014
Available online 25 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Arylnitration
Oxindoles
Dihydroquinolin-2(1H)-ones
C–H functionalization
Alkenes
Introduction
reaction of an alkyl halide with nitrite anion (NOꢀ2 ) has been
used.5g,h Moreover, addition of nitrogen dioxide to a C–C multiple
Oxindoles are ubiquitous heterocycles found in a wide range of
natural products, pharmaceuticals, and biologically active com-
pounds.1 In the past few years, a number of traditional processes
for the synthesis of these motifs have been established.2 Among
these methods, the transition-metal-catalyzed cyclization func-
tionalization of ortho-nonfunctionalized aniline derivatives has re-
ceived special attention due to the high atom economy. Buchwald
bond also affords corresponding aliphatic nitro compounds.5i-n In
addition, transition-metal-catalyzed synthesis of aromatic nitro
compounds from aryl chlorides, triflates, and nonaflates has also
been developed.5o-q However, despite progress in this area, exam-
ples of preparation of nitro compounds via alkene difunctionaliza-
tion strategy are quite rare. Taniguchi et al. have reported the
halonitration and hydroxylnitration of alkenes to give a variety of
substituted aliphatic nitro compounds.6 Very recently, we reported
a novel metal-free oxidative arylnitration of alkenes via nitration
and C–H functionalization cascade process.3q This methodology
provides an efficient way to construct nitro-containing oxindoles
and dihydroquinolin-2(1H)-ones. However, the efficiency for the
arylnitration of unactivated alkenes is low, and the yields of corre-
sponding dihydroquinolin-2(1H)-ones are not satisfactory. After
great efforts, we discovered that transformation could also occur
smoothly in the presence of AgNO3 and HOAc, and afford corre-
sponding products in good yields. Herein, we disclose our findings
(Scheme1).
and co-workers first used ortho-nonfunctionalized anilines (a-
chloroacetanilides) in the formation of oxindole through palla-
dium-catalyzed C–H functionalization.2c Subsequently, the groups
of Kündig2e and Taylor2f reported the copper-mediated direct
C(sp2)–H/C(sp3)–H functionalization of anilide to form a variety
of oxindoles through a radical process. Very recently, metal-medi-
ated and metal-free intramolecular difunctionalization of alkenes,
including aryloxygenation, arylalkylation, aryltrifluoromethyla-
tion, arylphosphination, and azidoarylation also provides an ele-
gant method for the construction of the oxindole skeleton.3
On the other hand, nitro compounds are widely used in various
fields such as medicine, industry, and fuels. Such compounds are
also valuable synthetic intermediates in organic chemistry.4 Classi-
cal nitration of aromatics anþd alkenes by electrophilic substitution
using nitronium cation (NO2 ) is well-known.5a-f As a method for
synthesis of aliphatic nitro compounds, nucleophilic substitution
Results and discussions
In an initial study, we chose the N-methyl-N-arylacrylamide 1a
as the model substrate to evaluate different nitrating source in the
presence of 10 equiv AcOH in CH3CN at 100 °C. To our delight,
when 3 equiv nitrates, such as Mg(NO3)2ꢁ6H2O, Cu(NO3)2ꢁ3H2O,
⇑
Corresponding author. Tel.: +86 871 65920747; fax: +86 871 65920570.
E-mail address: liym@kmust.edu.cn (Y.-M. Li).
http://dx.doi.org/10.1016/j.tetlet.2014.02.043
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2120
Y.-M. Li et al. / Tetrahedron Letters 55 (2014) 2119–2122
R2
NO2
O
With the optimized conditions in hand, we then set out to ex-
plore the scope and limitations of the above method, and the re-
sults are summarized in Table 2. Substrates bearing methyl and
benzyl protecting groups on the nitrogen were good for this trans-
formation, but unprotected N–H acrylamide failed to give the de-
sired product 2c. It indicated that the nitrogen protecting group
was essential under the reaction conditions. Tetrahydroisoquino-
line structural motif is commonly encountered in many biologi-
cally active compounds. Acrylamides prepared from this amine
provided the corresponding tricyclic oxindole derivative in excel-
lent yield under the developed reaction conditions (2d). A variety
of electron-donating and electron-withdrawing groups on the ani-
line moieties survived well in this transformation (2e–2g). How-
ever, amide with the methoxyl group at the para position of the
aromatic ring failed to afford the desired product 2h. Notably,
the halo-substituted N-methyl-N-phenylmethacrylamides were
tolerated and led to the corresponding halo-substituted nitro-con-
taining oxindoles in good yields (2i–2k). Substrates having two
substituents on the phenyl rings also reacted well with AgNO3
(2l, 2m). Satisfactorily, acrylamides bearing different functional
groups such as benzyl, acetoxymethyl, phthalimide, and azidoethyl
H
N
O
AgNO3
R3
R3
R2
N
R1
R1
Scheme 1. Arylnitration of alkenes.
Table 1
Optimization of reaction conditionsa
NO2
nitrate, HOAc
solvent
O
N
O
N
2a
1a
Entry
Nitrate (equiv)
Solvent
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
NaNO3 (3)
KNO3 (3)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
100
100
100
100
100
100
100
100
100
100
100
100
120
140
120
120
120
120
120
120
120
120
0
0
Mg(NO3)2ꢁ6H2O (3)
Cu(NO3)2ꢁ3H2O (3)
Y(NO3)3ꢁ6H2O (3)
Co(NO3)2ꢁ6H2O (3)
Ce(NO3)3ꢁ6H2O (3)
AgNO3 (3)
AgNO3 (3)
AgNO3 (3)
AgNO3 (3)
AgNO3 (3)
AgNO3 (3)
AgNO3 (3)
AgNO3 (3)
AgNO3 (3)
AgNO3 (3)
AgNO3 (3)
AgNO3 (4)
AgNO3 (2)
14
12
19
9
18
27
13
18
0
34
44
41
42
58
73
56
58
61
57
63
at the a-position also worked well, affording the products 2n–2q in
reasonable yields. It is noteworthy that the above reactions could
be extended to unactivated alkenes as well. The arylnitration pro-
ceeded smoothly to give the corresponding dihydroquinolin-
2(1H)-ones products in good to excellent yields (2r–2x). Moreover,
this transformation also enjoys the tolerance of a wide variety of
functional groups, including methyl, methoxyl, and halide, etc.
The detailed mechanism is still not clear, but this transforma-
tion might involve a free-radical process.3q Under the reaction con-
ditions, the nitrogen dioxide radical might be formed.6a,7 Addition
of the nitrogen dioxide radical to alkene gives carbon-centered rad-
ical intermediate, followed by intramolecular cyclization to afford
final product.
9
DMF
DMSO
Toluene
10
11
12
13
14
15c
16d
17e
18f
19e
20e
21e,g
22e,h
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
AgNO3 (3)
AgNO3 (3)
Conclusion
a
Reaction conditions: 1a (0.3 mmol) and nitrate, HOAc (10 equiv) in dry 1,4-
In summary, we have developed a novel and efficient arylnitra-
tion of alkenes by nitration and C–H functionalization cascade pro-
cess with AgNO3 and HOAc. In addition, the process exhibits
significant functional group tolerance and allows the synthesis of
structurally diverse nitro-containing oxindoles and dihydroquino-
lin-2(1H)-ones that are expected to be useful intermediates for
the preparation of pharmaceutically and biologically active com-
pounds as well as functional materials. Moreover, the use of inex-
pensive and readily available starting materials makes this
practical and atom-economical approach particularly attractive.
Further investigations toward the reaction scope, a detailed mech-
anism, and applications in organic synthesis are currently ongoing
in our laboratory.
dioxane (3 mL) with stirring at the given temperature for 24 h.
b
Isolated yield.
1.5 mL dioxane was used.
6 mL dioxane was used.
9 mL dioxane was used.
12 mL dioxane was used.
5 equiv HOAc.
15 equiv HOAc.
c
d
e
f
g
h
Y(NO3)3ꢁ6H2O, Co(NO3)2ꢁ6H2O, Ce(NO3)3ꢁ6H2O, and AgNO3 were
used, oxindole 2a was formed, and 2a was obtained in 27% highest
yield when AgNO3 was employed. But no product 2a could be ob-
served in the absence of NaNO3 or KNO3 (Table 1, entries 1–8).
Encouraged by the results, we then screened different solvents
such as DMF, DMSO, toluene, and 1,4-dioxane, and 1,4-dioxane
proved to be better than the others (entries 8–12). Among the reac-
tion temperatures examined, it turned out that the reaction at
120 °C gave the best results (entries 12–14). Notably, the concen-
tration of substrate 1a was important. Screening showed that
decreasing the concentration of 1a from 0.1 M to 0.033 M, the yield
of 2a improved from 44% to 73%, further decreasing the substrate
concentration resulted in a decrease in yield (entry 13 vs entries
15–18). The amount of nitrate and acid was also screened, the re-
sults show that 3 equiv AgNO3 and 10 equiv AcOH was the best
choice (entry 17 vs entries 19–22). Thus, entry 17 in Table 1 was
identified as the optimized reaction conditions.
Acknowledgments
We are grateful to the NSFC (Nos. 21072079 and 21272100) and
the Program for New Century Excellent Talents in University
(NCET-11-0215) for financial support.
Supplementary data
Supplementary data (Copies of 1H NMR, 13C NMR and 19F NMR
spectra of products. Experimental procedures and data for prod-
ucts.) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2014.02.043.

Y.-M. Li et al. / Tetrahedron Letters 55 (2014) 2119–2122
2121
Table 2
Scope of arylnitrationa,b
R2
NO2
n = 0, 1
O
H
3 equiv AgNO3
10 equiv HOAc
1,4-dioxane, 120 °C
O
R3
R3
N
R2
N
R1
n = 0, 1
R1
1a-1x
2a-2x
NO2
NO2
NO2
NO2
O
O
O
O
N
N
N
N
Bn
H
2a
, 73%
2b, 58%
2c
, 0%
2d
, 83%
NO2
NO2
NO2
NO2
F
F3C
MeO
O
O
O
O
N
N
N
N
2g
, 69%
2h, 0%
2e, 67%
2f, 76%
NO2
NO2
NO2
NO2
I
Cl
Br
O
O
O
O
N
N
N
N
2k
, 63%
2l, 65%
2i, 74%
2j, 66%
NPhth
NO2
OAc
OMe
Bn
N
NO2
NO2
NO2
O
O
O
O
N
N
N
MeO
2o
2p
, 57%
, 73%
NO2
2m, 79%
2n, 69%
NO2
N3
NO2
O
MeO
NO2
O
N
N
O
N
O
N
Bn
2s, 80%
2t, 38%
2r, 83%
2q
, 25%
NO2
O
NO2
O
NO2
O
NO2
O
Br
I
Cl
F
N
N
N
N
2u, 81%
2v, 78%
2x, 72%
2w, 81%
a
All the reactions were carried out in the presence of 0.3 mmol of 1a–1x, AgNO3 (3 equiv) and HOAc (10 equiv) in 9 mL 1,4-dioxane at 120 °C.
Isolated yield.
b
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