Hydrazonyl Radical-Participated Tandem Reaction: A Strategy for the Synthesis of Pyrazoline-Functionalized Oxindoles

Article abstract of DOI:10.1021/acs.orglett.5b03003

An efficient and practical tandem cyclization/addition/cyclization strategy is developed for the initial generated hydrazonyl radicals derived from the oxidation of β,γ-unsaturated hydrazones. By using this protocol, structurally novel pyrazoline-functionalized oxindoles are prepared by the reaction of easily accessible β,γ-unsaturated hydrazones with N-aryl acrylamides under the metal- and solvent-free conditions of DTBP (di-tert-butyl peroxide) via a tandem intra/intermolecular C-N/C-C/C-C bond formation.

Full text of DOI:10.1021/acs.orglett.5b03003

Letter
pubs.acs.org/OrgLett
Hydrazonyl Radical-Participated Tandem Reaction: A Strategy for the
Synthesis of Pyrazoline-Functionalized Oxindoles
Xiao-Yong Duan, Xiu-Long Yang, Pan-Pan Jia, Man Zhang, and Bing Han*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou,
730000, P. R. China
S
* Supporting Information
ABSTRACT: An efficient and practical tandem cyclization/
addition/cyclization strategy is developed for the initial generated
hydrazonyl radicals derived from the oxidation of β,γ-unsaturated
hydrazones. By using this protocol, structurally novel pyrazoline-
functionalized oxindoles are prepared by the reaction of easily
accessible β,γ-unsaturated hydrazones with N-aryl acrylamides under
the metal- and solvent-free conditions of DTBP (di-tert-butyl peroxide) via a tandem intra/intermolecular C−N/C−C/C−C
bond formation.
ree radical chemistry has ushered in a new epoch in the
evolution of chemistry, and it has become an important and
Scheme 1. Strategy for the Hydrazonyl Radical Participated
Cascade Cyclization/Addition/Cyclization
F
effective tool in organic synthesis in the recent decades.1 Among
the diverse free radical-mediated synthetic methodologies,
strategy utilizing free radical tandem reactions has proven to be
highly valuable for the synthesis of complex carbo- and
heteropolycyclic skeletons because of their highly synthetic
efficiency and simple operation.2
Hydrazonyl radical, as a kind of fascinating nitrogen-centered
radical,3 which can be easily initiated from the most common
hydrazone, has not received the attention it deserves, and its
considerable synthetic potential has remained largely unappre-
ciated.4 Very recently, we and other groups have developed a
series of hydrazonyl radical-involved cyclization reactions for the
synthesis of pyrazoline derivatives.5 However, the research is far
from exhaustive and much remains to be explored. In our
continuous interest in the hydrazonyl radical-based reactions for
a synthetic purpose, herein we wish to report an efficient and
practical hydrazonyl radical-participated cascade cyclization/
addition/cyclization strategy for the preparation of pyrazoline-
functionalized oxindoles from easily accessible β,γ-unsaturated
hydrazones and N-aryl acrylamides. We anticipated that the
carbon-centered radical derived from the β,γ-unsaturated
hydrazonyl radical 5-exo-trig cyclization would undergo inter-
molecular addition to the carbon−carbon double bond of N-aryl
acrylamide to produce a deuterogenic carbon-centered radical
adduct; the latter further cyclized to the adjacent N-phenyl via
intramolecular aromatic homolytic substitution6 to yield pyrazo-
line-functionalized oxindole (Scheme 1). Recently, N-aryl
acrylamides have proven to be efficient radical acceptors,7 and
it was expected that the intermolecular radical addition in our
synthetic design would proceed as well.
ingly, these two classes of compounds have attracted much
interest from synthetic and pharmaceutical chemists. In this
context, the present protocol affords an efficient method for the
synthesis of structurally novel pyrazoline-functionalized oxin-
doles, which possess latent biochemical and pharmaceutical
properties as well as a tandem process for the intra/
intermolecular C−N/C−C/C−C bond formation involving
both activated and unactivated alkenes.
To test the assumption, the reaction of N-methyl-N-phenyl
methacrylamide (1a, 0.5 mmol) with N-phenyl-β,γ-unsaturated
hydrazone (2a, 1.0 mmol) under oxidative conditions was
chosen as a model reaction for the optimization investigation
(Table 1). First, TBHP (tert-butyl hydroperoxide, 70% aqueous)
was tested as the oxidant, but hydrazone 1a was hydrolyzed to the
corresponding ketone with the desired product 3a undetected
(Table 1, entry 1). Next, when TBHP (5−6 M in decane) was
used in the reaction, the desired product 3a was obtained in 34%
yield (Table 1, entry 2). Remarkably, treatment of 1a and 2a with
DTBP (di-tert-butyl peroxide) led to the product 3a in 71% yield
(Table 1, entry 3). The use of other oxidants such as TBPB (tert-
butyl peroxybenzoate), BPO (benzoyl peroxide), and AIBN
Pyrazoline derivatives are known to possess potent biological
activities, including antiproliferative, antimalarial, and antibacte-
rial activities.8 On the other side, oxindoles are important
heterocyclic scaffolds that exist in a wide range of natural
products, pharmaceuticals, and bioactive molecules.9 Accord-
Received: October 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03003
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
ab c
, ,
Table 1. Optimization for the Tandem Reaction
Scheme 3. Scope of N-Aryl Acrylamides
b
entry
oxidant (equiv)
solvent
t (°C)
%, yield
c
1
2
3
4
5
6
7
TBHP (4.0)
neat
100
100
100
100
100
100
100
120
trace
34
d
TBHP (4.0)
neat
DTBP (4.0)
TBPB (4.0)
BPO (4.0)
neat
71
neat
45
toluene
toluene
neat
trace
16
AIBN (4.0)
DTBP (6.5)
DTBP (6.5)
88
e
8
neat
67
a
Reaction conditions: a mixture of 1a (0.5 mmol, 1 equiv), 2a (1.0
mmol, 2 equiv), and solvent (0.5 mL) was stirred under an argon
b
c
atmosphere. Yield of isolated products. TBHP (70% aqueous).
d
e
TBHP (5−6 M in decane). After 48 h.
(2,2-azobisisobutyronitrile) did not provide better results (Table
1, entries 4−6). Gratifyingly, with the increase of the usage
amount of DTBP to 6.5 equiv, the yield of 3a was increased to
88% (Table 1, entry 7). In order to shorten the reaction time, we
attempted to heat the reaction system up to 120 °C, but the result
was rather disappointing (Table 1, entry 8).
To identify that the generation of hydrazonyl radical was the
initial step, a control experiment was carried out as shown in
Scheme 2. When the carbon-centered radical scavenger TEMPO
a
Reaction conditions: a mixture of 1 (0.5 mmol, 1 equiv), 2a (1.0
mmol, 2 equiv), and DTBP (3.25 mmol, 6.5 equiv) was stirred at 100
b
c
°C under argon in neat for 72 h. Yield of isolated products. Ratios in
parentheses indicate the diastereomers, and they were determined by
1H NMR spectroscopy.
Scheme 2. Control Experiment
1). When N-methyl methacrylamides bearing pyridine and
naphthalene were involved in the reaction, the expected products
(2,2,6,6-tetramethylpiperidin-1-oxyl) was added in the reaction
under the standard reaction conditions, the desired compound
3a was not detected but the pyrazoline 4, which was obviously
yielded from the trapping of the C-centered radical derived from
the hydrazonyl radical fast 5-exo-trig cyclization by TEMPO, was
formed as the sole product in 96% yield. This observation
demonstrated clearly that the initiation step is the generation of
the hydrazonyl radical.
With the optimal conditions in hand (Table 1, entry 7), the
scope of N-aryl acrylamides 1 was tested to react with N-phenyl-
β,γ-unsaturated hydrazone 2a, and the results are listed in
Scheme 3. Acrylamides with various N-protecting groups, such as
N-Me, N-Bn, and N-CH2COOEt, were tolerated well to afford
the desired pyrrazoline-functionalized oxindoles in good yield
(3a−c). However, the N-acetyl and N-unprotected acrylamides
did not work (3d−e). When the substrate bearing Bn (benzyl
group) at the 2-position of the acrylamide moiety participated in
the tandem reaction, the corresponding product 3f was also
gained in 65% yield. Then, the substituent effects on the aromatic
ring of N-aryl acrylamides were also studied. Screening showed
that several substituents, such as p-Me, p-Cl, p-Ph, o-Me, and o-Br
groups, were well tolerated under the optimal conditions and
delivered the corresponding products in good to excellent yields
(3g−k). Significantly, in the case of o-Br substituted N-methyl-
N-phenyl methacrylamide, the acquired diastereoisomers could
be separated as 3k and 3k′ in a ratio of 1.25:1. The structure of 3k
was confirmed by a single-crystal X-ray diffraction study (Figure
Figure 1. X-ray structure of 3k (thermals ellipsoids are shown with 30%
probability).
3l and 3m were afforded in 56% and 76% yield, respectively.
Notably, a larger tetracyclic oxindole derivative 3n was also
successfully prepared in 72% yield with this protocol.
Having successfully achieved the tandem reaction with N-aryl
acrylamides, we then shifted our attention to explore the scope of
β,γ-unsaturated ketohydrazones (Scheme 4). N-Phenyl with a
range of electronic properties substituted β,γ-unsaturated
ketohydrazones all proceeded well in the reaction to yield the
desired pyrazoline-functionalized oxidoles in excellent yields
(3o−r). In addition, N-alkyl substituted ketohydrazone was also
tolerated in the reaction and gave the corresponding product 3s
in 55% yield. However, N-acetyl and N-tosyl substituted
ketohydrazones were inert in the reaction probably due to
their strong N−H bond (3t−u). β,γ-Unsaturated N-phenyl
B
DOI: 10.1021/acs.orglett.5b03003
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b c
, ,
Scheme 4. Scope of β,γ-Unsaturated Ketohydrazones
Scheme 6. Plausible Mechanism for Hydrazonyl Radical-
Participated Tandem Reaction
addition of the C-centered radical II to the carbon−carbon
double bond of N-aryl acrylamide 1 produces the deuterogenic
C-centered radical adduct III, which ulteriorly cyclizes to the
adjacent phenyl ring to yield the cyclohexadienyl radical IV.
Finally, further oxidative aromatization of the cyclohexadienyl
radical IV by DTBP gives the desired product 3.
In conclusion, a novel and efficient metal- as well solvent-free
protocol has been developed for the synthesis of structurally
novel pyrazoline-functionalized oxindoles via tandem cycliza-
tion/addition/cyclization sequence using β,γ-unsaturated hydra-
zones and N-aryl acrylamides as the easily prepared substrates
and DTBP as the commercially available oxidant. To the best of
our knowledge, this study represents the first example of using
DTBP as the oxidant for the initiation of hydrazonyl radical as
well as the first example of hydrazonyl radical-participated one-
pot tandem intra/intermolecular C−N/C−C/C−C bond
formation involving both activated and unactivated alkenes.
Further studies on the hydrazonyl radical promoted reaction are
in progress in our laboratory.
a
Reaction conditions: a mixture of 1a (0.5 mmol, 1 equiv), 2 (1.0
mmol, 2 equiv), and DTBP (3.25 mmol, 6.5 equiv) was stirred at 100
b
c
°C under argon in neat for 72 h. Yield of isolated products. Ratios in
parentheses indicate the diastereomers, and they were determined by
1H NMR spectroscopy.
ketohydrazones bearing aryls such as substituted phenyls,
naphthyl, thiophene, and indole participated smoothly in the
tandem reaction as well, giving rise to the corresponding
pyrazoline-functionalized oxindoles in good to excellent yields
(3v−ab). Moreover, alkyl incorporated N-phenyl ketohydrazone
was transformed to the desired product 3ac in 81% yield.
In addition, when γ,δ-unsaturated hydrazone 2q was reacted
with 1a, the tetrahydropyridazine-functionalized oxindoles 5 was
obtained in 42% yield (Scheme 5). This observation is consistent
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03003.
Detailed experimental procedures and spectral data for all
products (PDF)
Compound 3k (CIF)
Scheme 5. γ,δ-Unsaturated Ketohydrazone-Participated
Tandem Reaction with N-Phenylmethacrylamide
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hanb@lzu.edu.cn
Notes
The authors declare no competing financial interest.
with our previous findings that γ,δ-unsaturated hydrazone-
derived hydrazonyl radicals are suitable for the N atom 6-exo-trig
cyclization; therefore, the present protocol is also convenient to
synthesize tetrahydropyridazine-functionalized oxindole deriva-
tives.
To account for the aforementioned results, a mechanism was
proposed as shown in Scheme 6. DTBP first decomposes to
produce t-BuO radical under the condition of heating; the latter
initiates hydrazone 2 to the corresponding hydrazonyl radical I
via a HAT (hydrogen atom transfer) process. The hydrazonyl
radical I subsequently undergoes fast 5-exo-trig cyclization to
yield the corresponding C-centered radical II. Intermolecular
ACKNOWLEDGMENTS
■
We thank the NNSFC (21422205, 21272106), the Program for
New Century Excellent Talents in University (NCET-13-0258),
the “111” project, and the Fundamental Research Funds for the
Central Universities (lzujbky-2014-k03, lzujbky-2014-60,
lzujbky-2014-238) for financial support.
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