Metal-free Synthesis of β-Nitrostyrenes via DDQ-Catalyzed Nitration

Full text of DOI:10.1002/bkcs.12232

Communication
DOI: 10.1002/bkcs.12232
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S. Park et al.
KOREAN CHEMICAL SOCIETY
Metal-free Synthesis of β-Nitrostyrenes via DDQ-Catalyzed Nitration
Sangwoon Park,† Seungri Yoon,† and Sun-Joon Min†,‡,
*
†Department of Applied Chemistry, Center for Bionano Intelligence Education and Research, Hanyang
University, Ansan, Gyeonggi-do, 15588, Republic of Korea
‡Department of Chemical and Molecular Engineering, Hanyang University, Ansan, Gyeonggi-do, 15588,
Republic of Korea. *E-mail: sjmin@hanyang.ac.kr
Received December 11, 2020, Accepted January 12, 2021, Published online February 14, 2021
Nitrostyrenes are an important class of intermediates in syn-
thetic organic chemistry, which are widely used for the syn-
thesis of versatile building blocks in material or
pharmaceutical chemistry.1 For example, p-chloronitrostyrene
derivative exhibited antitumor activity through inhibition of
protein phosphatase.1e They are often used as versatile sub-
strates for C C bond forming reactions such as the Morita–
Baylis–Hillman reaction, the Michael reaction, and cycloaddi-
tion reaction.2 One of the classical synthetic methods for
nitroalkenes is the Henry reaction followed by dehydration of
the resultant β-nitro alcohols.3 Alternatively, the direct incor-
poration of nitro group into readily available alkenes provides
more convenient and efficient access to β-nitrostyrenes, which
has been studied by many synthetic groups. In the early
researches, these synthetic methods required metal nitrates or
NOx gases as a source of nitrating agents.4,5 However, they
have some drawbacks, such as the low selectivity to E- and
Z-isomers, limited scope of substrates and harsh reaction con-
ditions. Most recently, several research groups overcome such
problems by using appropriate combination of nitrogen
sources and mild oxidants under transition-metal free condi-
tions (Scheme 1).6–8 Maiti et al. developed the practical
stereoselective nitration of styrenes with tert-butyl nitrite
(TBN) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO).6
Guo group also reported the nitration reactions of olefins with
sodium nitrite, K2S2O8 using TEMPO.7 TEMPO served as an
important reagent for hydrogen abstract in both reactions.
Singh et al. published another simple stereoselective formation
of nitrostyrenes using sodium nitrite and K2S2O8 in the pres-
ence of trifluoroacetic acid as well.8 All of these reactions
granted an easy preparation of β-nitrostyrenes, but it is neces-
sary to execute the reactions at high temperature or use stoi-
chiometric amounts of oxidants or strong acid.
be suitable for development of a mild reaction condition as
well as our proposed nitration process.11
Herein, we report the synthesis of β-nitrostyrenes under
mild aerobic condition using DDQ as a catalyst.
We initially investigated aerobic nitration of styrenes
under various reaction conditions in the presence of DDQ
as a catalyst. The results are demonstrated in Table 1. First,
the reaction of styrene 1a with TBN (2.0 equiv.) and DDQ
(0.2 equiv.) in CH3CN at room temperature afforded the
corresponding (E)-β-nitrostyrene 2a in 70% yield (entry 1).
The stereochemistry of 2a was determined by the analysis
of proton NMR, in which the coupling constant of two ole-
finic protons was 13.7 Hz. When we increased the amount
of DDQ up to 0.5 equivalent, the yield was improved to
90% and the reaction time was significantly reduced as well
(entries 2–4). Additionally, we screened several solvent
systems such as THF, CH2Cl2, N,N-dimethylformamide
(DMF), dimethyl sulfoxide (DMSO) and EtOH to study
solvent effect on our nitration reaction. We observed rela-
tively lower yields in most cases (entries 5–8) and no prod-
uct was obtained when we performed the reaction in EtOH
(entry 9). As control experiments, we found that the reac-
tion in the absence of DDQ produced styrene 2a only in
24% yield (entry 10) and the use of one equivalent TBN
gave lower yield compared to that of the reaction under the
optimized condition (entry 11). We also proved that the
reaction did not proceed in the presence of radical scaven-
ger (entry 12) and without air (entry 13). These overall
results suggest that the nitration occurs through radical
mechanism and TBN is not only a source of nitro radical,
but also a crucial oxidant for conversion of DDQH2 to
DDQ during the catalytic process. On the other hand, we
cannot rule out the mechanistic possibility of stoichiometric
reaction with 0.5 equivalent of DDQ because DDQ should
be involved twice in the catalytic cycle suggested in
Scheme 2. Further mechanistic studies are currently under-
way in our laboratory.
DDQ is an important oxidant for various reactions under
mild and metal free condition.9 Accordingly, we envisioned
that DDQ, as an essential oxidant, could be involved in
either a hydrogen atom transfer process or a single electron
transfer process in the nitration reaction of styrenes with
TBN as shown in Scheme 2. In this concept, TBN serves
as a crucial nitrating agent,10 of which homolytic cleavage
by any hydrogen source might accelerate generation of NO
radical at room temperature. Thus, the use of DDQ would
Next, we examined the scope of our nitration process
using a series of substituted styrenes possessing different
electronic characters on phenyl ring (Scheme 3). In general,
the nitration reactions of electron-rich styrenes such as
methyl styrene and chloromethyl styrene produced the
corresponding β-nitrostyrenes (2b, 2i, and 2j) in good
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Scheme 1. Reported synthetic methods of β-nitrostyrenes via
radical-mediated nitration.
Scheme 2. Overview of DDQ-catalyzed nitration in this work.
Table 1. Optimization of stereoselective nitration reactions.
Scheme 3. Formation of various β-nitrostyrenes.
yields. However, the reaction of 4-methoxy styrene 1h
under the optimized condition proceeded to give compound
2h in low yield, which resulted from decomposition of the
product during the reaction. In case of halogen-substituted
styrenes, we obtained β-nitrostyrenes derivatives 2c-g in
good to moderate yields regardless of a class of halogen
and the substituent position. It is noteworthy that
α-methylstyrene 1k underwent the nitration reaction to
afford only (E)-nitro olefin 2k as a single stereoisomer
although the yield is relatively moderate. On the other
hand, when cyano styrene 1l, dihydronaphthalene 1m, and
2-vinylnaphthalene 1n were used as substrates, we
observed poor yields (less than 10%) of the desired prod-
ucts 2l-n. This result indicated that the electron-poor aro-
matic ring system or the conformational restriction may not
effectively stabilize the radical intermediate generated dur-
ing the reaction process (see intermediate 3 in Scheme 1).
To extend our protocol to synthesize aliphatic or hetero-
aromatic nitroalkenes, we attempted the nitration reactions
of several alkenes as shown in Scheme 4. The nitration of
octene and allylbenzene under our standard condition pro-
duced the corresponding nitroalkenes 5a and 5b in 56%
and 37%, respectively, whereas no desired nitroalkene (5c)
was isolated from (S)-(−)-limonene. On the basis of this
result, our nitration reaction would be appropriate only for
Entry
DDQ (equiv.)
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
0.2
0.3
0.4
0.5
0.5
0.5
0.5
0.5
0.5
CH3CN
CH3CN
CH3CN
CH3CN
THF
CH2Cl2
DMF
DMSO
EtOH
CH3CN
CH3CN
CH3CN
CH3CN
6
4
4
2
18
18
18
18
18
6
70
70
80
90
73
34
34
9
b
9
-
c
10
11d
12e
13g
-
24
59
0.5
0.5
0.5
2
2
2
f
-
-
f
a Isolated yields.
b Only trace amount of product was observed.
c The reaction was performed without DDQ.
d The reaction was performed with one equivalent of TBN.
e The reaction was performed in the presence of butylated
hydroxytoluene.
f No reaction.
g The reaction was performed without air.
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indole to the synthesized β-nitrostyrenes. The study on a
practical synthesis of biologically active β-nitrostyrenes
using this strategy is currently in progress.
Acknowledgment. This work was supported by the National
Research Foundation of Korea (NRF) grant funded by the
Korea government (MSIT) (NRF-2019R1A2C1008186 and
2020R1A4A4079870).
Supporting Information. Additional supporting informa-
tion may be found online in the Supporting Information
section at the end of the article.
Scheme 4. Extension and limitation of substrate scope.
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