Metal-free nitro-carbocyclization of activated alkenes: A direct approach to synthesize oxindoles by cascade C-N and C-C bond formation

Article abstract of DOI:10.1039/c3cc47336h

A novel and direct metal-free nitro-carbocyclization of activated alkenes leading to valuable nitro-containing oxindoles via cascade C-N and C-C bond formation has been developed. The mechanistic study indicates that the initial NO and NO₂ radical addition and the following C-H functionalization processes are involved in this transformation. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3cc47336h

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Metal-Free Nitro-Carbocyclization of Activated Alkenes: Direct Approach to Oxindoles by Cascade C-N
and C-C Bond Formation**
Tao Shen,a Yizhi Yuan,a and Ning Jiao*,a,b
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A novel and direct metal-free nitro-carbocyclization of
been reported till this work and are in high demand. 2) The metal
activated alkenes leading to valuable nitro-containing 45 free and mild conditions make it a convenient way to prepare
oxindoles via cascade C-N and C-C bond formation has been
10 developed. The mechanistic study indicates that the initial NO
and NO2 radical addition and the following C-H
nitrogenꢀcontaining compounds. 3) The mechanistic study
indicates that the initial NO and NO2 radical addition and the
following CꢀH functionalization processes are involved in this
transformation.
NꢀmethylꢀNꢀarylacrylamide 1a was initially investigated as
the model substrate for the direct carbonitration of activated
functionalization
transformation.
processes
are
involved
in
this
50
As an importantclass of biological organic compounds,
15 nitrogenꢀcontaining moleculeshave been widely used as
alkenes.
Gratifyingly,
the
desired
1,3ꢀdimethylꢀ3ꢀ
functional
materials,
synthetic
intermediates,
and
(nitromethyl)indolinꢀ2ꢀone 2a was isolated in 31% yield by
using 2.0 eq Fe(NO3)3·9H2O as NO2 source in MeCN (Table
pharmaceuticals.1 Nitro compounds are also important and
useful precursors for the corresponding functional molecules
such as amines and ketones. Therefore, many nitration
20 methodologies for the synthesis of aromatic and aliphatic nitro
compounds have been developed.2,3 As one of the most
attractive topics in organic chemistry, the activation of inert
CꢀH bonds has drawed interests of chemists in the past
decades.4 Moreover, recently the transition metal – free C–H
25 functionalization reactions has arrtacted more attentions due
to the economical and environmental viewpoints.5 Under this
concept, some examples of sp2 CꢀH activition via radical
pathway for the synthesis of oxindoles which are a large class
of natural products withunique biological activity and
30 represent one of the privileged scaffolds for library design and
55 1, entry 1). Encouraged by this result, we further optimized
the reaction conditions by changing the NO2 source. When t-
BuONO was employed as the nitrogen source, the desired
oxindole was obtained in 44% yield (Table 1, entry 5).
Although few solvents did not promote the efficiency of the
60 desired transformation (Table 1, entries 6 ꢀ 11), DMF was
found to be superior with 68% yield for 2a (Table 1, entries
12). To our delight, when the loading of t-BuONO was
increaced to 2.5 eq with two portions addition, the yield of 2a
was improved to 74% yield (Table 1, entry 14).
65 Table 1. Optimization for the direct carbonitration of activated
alkenesa
drug
discovery,6,7
have
been
significantly
disclosed.8,9Although some elegant works on NO2 radical
trapped by alkenes have been achieved,10 the metal free direct
tandem nitration and CꢀH functionalization still remains
35 challenge.
a
Reaction conditions: 1a (0.2 mmol) and t-BuONO(0.4 mmol) in dry
DMF (2 mL) with stirring at 100℃ for 24 h. Isolated yieldb 10% TEMPO
70 was used. c2.5 eq of t-BuONO was used and was added into two portions.
Scheme 1. The metalꢀfree CꢀH nitrification of activated alkenes
Herein, we report a novel and direct metalꢀfree nitroꢀ
carbocyclization of activated alkenes leading to oxindoles via
40 cascade CꢀN and CꢀC bond formation (Scheme 1). The
significance of the present chemistry is threefold: 1) To our best
of knowledge, the addition of the NO2 radical to alkenes followed
by a CꢀH functionalization for the synthesis of oxindoles has not
To explore the scope of this carbonitration of alkenes,
various N-arylacrylamides were subjected to the optimized
reaction conditions to prepare. 3ꢀsubstituted oxindoles(Table
2) which are a large class of natural products with unique
75 biological activity
a
wide range of natural products,
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[journal], [year], [vol], 00–00 |1

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pharmaceuticals, and agrochemicals and represent one of the
privileged scaffolds for drug discovery and library design.11In
finished in 24 h under standard reaction conditions, 18O2 was
filled in reaction system and went on reaction for 12 h at room
general, very smooth nitroꢀcarbocyclization progress occurred 40 temperature. The ratio of 16O product and 18O product is 5:1 (Eq.
for N-arylacrylamides having substituents at para and meta
aswell as ortho positions in the aniline. Substrates bearing an
electronꢀdonating groups (e.g., Me, tꢀBu, OMe) or a strong
electronꢀwithdrawing group (e.g., CF3 and CO2Me) at the aryl
12, see SI), which indicated that one pass way for the process
may the addition of generated NO radical from tꢀBuONO is
followed by O2 oxidation in the subsequent processing. Besides,
when 2.0 eq H218O was added under the standard reaction
5
ring are tolerant in this transformation. It is noteworthy that 45 conditions, The ratio of 16O product and 18O product turned to be
the haloꢀsubstituted (F, Cl, Br, I) NꢀmethylꢀNꢀ
1:1 (Eq. 2, see SI), which suggested that maybe H2O promoted
the generated of NO2 radical, and NO2 radical is prior to add to
alkenes rather than NO radical. In contrast, when 2a was heated
under 18O2 or in H218O, the 18O labeled product was hardly
10 phenylmethacrylamides worked well to afford the
corresponding haloꢀsubstituted oxindoles in good yields(2c,
2d, 2h, 2i). To our delight, cyclization of the
tetrahydroquinoline derivative furnished the tricyclic oxindole 50 observed (see SI). These control experiments may exclude the
2p in 77% yield. Moreover, the unactivated alkenes can also
15 undergo carbonitration smoothly, generating corresponding
products in moderate yields (2t). Polysubstituted derivatives
provided carbonitration oxindoles in good yields (Table 2, 2r).
Unfortunately, when change the frameworks of the substrates
by replacing the heteroatoms from N to O, no desired product
20 was obvserved (Table 2, 2v, 2x).
possible exchange after the product generation.
a
Table 2 Metalꢀfree CꢀH nitrification of activated alkenes.
NO2
Scheme 2
H
t-BuONO ( 2.5 eq)
O
n=0.1
O
DMF, 100 C, 24 h
N
N
n=0.1
To look insight the catalytic procedure, the intramolecular
55 and intermolecular kinetic isotope effect (KIE) experiments
were carried out with the deuteriumlabeled substrates [D1]ꢀ1a
and [D5]ꢀ1a (Eq. 3ꢀ4). Two secondary kinetic isotope effects
were observed (the intramolecular KH/KD=1.1, and
intermolecular KH/KD=1.0).
2
1
NO2
NO2
NO2
Br
NO2
Cl
Me
O
O
O
O
N
N
N
N
2d 62%
2a 74%
2b 68%
2c 76%
OAc
NO2
NO2
NO2
I
MeOOC
MeO
NO2
O
O
O
O
N
N
N
N
60
2g 48%
2e 74%
2h 68%
2f 75%
NO2
O
NO2
O
O
standard conditions
NO2
NO2
NO2
NO2
F3CO
+
F
(3)
N
N
24.0 h, 77% yield
N
O
O
O
O
D
KH/KD = 1.1
D
N
N
N
N
Et
2a-d1
1a-d1
2a
Ph
2l 56%
2j 80%
2i 81%
2k 54%
Ph
NO2
NO2
NO2
1a
+
NO2
t-Bu
D
D
1a: 1a-d5 = 1:1
standard conditions
NO2
O
O
NO2
O
D
D
O
(4)
N
N
Bn
D
O
+
N
Boc
N
O
1.0 h, 44% yield
N
D
D
D
N
O
2n 48%
2m 67%
KH/KD = 1.0
2o 50%
2p 77%
2a
N
2a-d5
NO2
NO2
NO2
F
NO2
D
O
1a-d5
O
O
N
N
N
N
O
F
F
2
2s 42%
NO2
2r 31%
2q 52%
NO2
2t 51%
NO2
NO2
On the basis of these preliminary results, two possible
mechanisms are proposed (Scheme 2). Initially, generation of
NO from tertꢀbutyl nitrite and its conversion to the NO2
65 radical under aerobic conditions has strong literature
precedent.14 Morever, trace amount O2 and H2O could also
promote this transformation(a, Scheme 2).3d,14c Then the NO2
radical addition to the activated alkenes 1a generates radical
intermediate A, followed by intramolecular carbocyclization
70 affording radical intermediate B, which is oxidized by NO2 to
generate 2a via a SET process. Alternatively, another process
with the NO radical addition could not be excluded (b,
Scheme 2). The generated NO radical from tertꢀbutyl nitrite
directly attacks 1a to give radical intermediate D, which
75 undergoes intramolecular carbocyclization to generate radical
E. Further single electron oxidation of E by NO2 radical
affording NO substituted oxindole F which is very active and
easily oxidized by air to afford the desire product 2a in the
subsequent purification processing.16
O
O
O
N
O
N
O
Boc
2v 0%
Ph
2w 0%
2u 44%
2x 0%
aReaction conditions: 1 (0.2 mmol) and tꢀBuONO (0.5 mmol) in DMF (2
25 mL) at 100 oC under Ar for 24 h. Isolated yields are reported.
In the reported nitration reactions of alkenes with t-BuONO,
it is well known to proceed by a radical process.12,13 When the
reaction was trapped by TEMPO, the carbonitration process
30 was suppressed and only trace amount product obtained (Eq.
S1, see SI). Besides, the corresponding oxime, which could be
converted to nitro compound by some oxidants,15 failed to
give nitro compound under O2 or the standard conditions (see
SI), which may exclude oxime as an intermediate involved in
35 this transformation. Furthermore, to interpret why oxidation
product 2a could be obtained under Ar in high yield, some 18O
labeled experiments were tested. After ensured the reaction
2
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DOI: 10.1039/C3CC47336H
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50
5
For some recent examples of transition metalꢀfree C–H
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55
6
60
7
For some reported synthesis of oxindoles from aniline derivatives in
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Ashida, M. Murakami, Org. Lett. 2011, 13, 1666; (e) C. Dey, D.
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Scheme 2 Proposed mechanisms
65
In conclusion, we have developed a highly efficient protocol
for the preparation of various biologically interesting nitro
oxindoles by metal free nitroꢀcarbocyclization of activated
alkenes via cascade CꢀN and CꢀC bond formation. The
mechanistic study indicates that both of the NO and NO2 radical
addition are involved in this transformation. NO2 radical addition
is prior than NO radical addition to the activated alkene. Further
70
75
80
85
90
5
8
9
For some transition metalꢀmediated radical synthesis of oxindoles
from aniline derivatives, see: (a) W.ꢀT. Wei, M.ꢀB. Zhou, J.ꢀH. Fan,
W. Liu, R.ꢀJ. Song, Y. Liu, M. Hu, P. Xie and J.ꢀH. Li, Angew.
Chem. Int. Ed. 2013, 52, 3638; (b) Y.ꢀ M. Li, M. Sun, H.ꢀL.Wang,
Q.ꢀP. Tian and S.ꢀD. Yang, Angew. Chem. Int. Ed.2013, 52, 3972.
For some metalꢀfree radical synthesis of oxindoles from aniline
derivatives, see: (a) M.ꢀB. Zhou, R.ꢀJ. Song, X.ꢀH. Ouyang, Y. Liu,
W.ꢀT. Wei, G.ꢀB. Deng and J.ꢀH. Li, Chem. Sci. 2013, 4, 2690; (b)
K. Matcha, R. Narayan and A. P. Antonchick, Angew. Chem. Int. Ed.
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Xiao and C. Zhou, J. Org.Chem. 2013, 78, 7343;
10 studies on the clarification of the reaction mechanism and
application of this transformation are undergoing.
Acknowledgment
Financial support from National Science Foundation of China
(No. 21172006), and the Ph.D. Programs Foundation of the
15 Ministry of Education of China (No. 20120001110013) are
greatly appreciated. We thank Miancheng Zou in this group for
reproducing the results of 2c and 2e.
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Notes and references
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T. Shen, Y. Yuan, and N. Jiao*
Metal-Free Nitro-Carbocyclization of Activated
Alkenes: Direct Approach to Oxindoles by Cascade
C-N and C-C Bond Formation
A direct nitro-carbocyclization of activated alkenes leading to nitro-
containing oxindoles via cascade C-N and C-C bond formation has been
developed.