1,3-Difunctionalization of β-alkyl nitroalkenes via combination of Lewis base catalysis and radical oxidation

Article abstract of DOI:10.1021/acs.orglett.0c04106

Upon treatment with a Lewis base catalyst, β-alkyl-substituted nitroalkenes could be readily converted into allylic nitro compounds. Examples of either C-1 or C-3 functionalization methods have been reported through nitro-elimination, giving alkene products. In this work, successful 1,3-difunctionalization was achieved through a synergetic Lewis base catalysis and TBHP radical oxidation, giving vinylic alkoxyamines in good to excellent yields. This work further extended the general synthetic application of β-alkyl nitroalkenes.

Full text of DOI:10.1021/acs.orglett.0c04106

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Letter
1,3-Difunctionalization of β‑Alkyl Nitroalkenes via Combination of
Lewis Base Catalysis and Radical Oxidation
Ye Wang, Lei Zheng, Xiaodong Shi,* and Yunfeng Chen*
Cite This: Org. Lett. 2021, 23, 886−889
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ABSTRACT: Upon treatment with a Lewis base catalyst, β-alkyl-
substituted nitroalkenes could be readily converted into allylic nitro
compounds. Examples of either C-1 or C-3 functionalization methods
have been reported through nitro-elimination, giving alkene products. In
this work, successful 1,3-difunctionalization was achieved through a
synergetic Lewis base catalysis and TBHP radical oxidation, giving
vinylic alkoxyamines in good to excellent yields. This work further
extended the general synthetic application of β-alkyl nitroalkenes.
oxide, etc.4 To further extend the utility of β-alkyl nitroalkenes,
itroalkene has been widely applied as a good Michael
Nacceptor for the selectively nucleophilic addition on β- we recently explored the LB-catalyzed nitroalkene trans-
formation involving a single-electron process.5 As shown in
Scheme 1B, we found that the addition of a sulfonyl radical to
the allylic nitro compound 1a′ is favored over nitroalkene 1a.
Followed by sequential nitro-elimination, the sulfonyl group
was selectively introduced at the C-3 position. With a strong
interest in understanding the reaction mechanism and
initiating an alterative activation mode of β-alkyl nitroalkene,
we explored the possibility of its difunctionalization. Herein,
we reveal a successful example using TEMPO as the radical
trapping reagent to achieve 1,3-difunctionalization of β-alkyl
nitroalkene through synergistic Lewis base and radical redox
catalysis,6 giving vinylic alkoxyamines in good to excellent
yields (Scheme 1C).7
carbon.1 Over the past decades, our group has been working
on the application of β-alkyl-substituted nitroalkenes as a
versatile synthon in organic transformations.2 The key design
factor was employment of the C-3 proton that will advance β-
H elimination of a Lewis base (LB) catalyst to access the
catalyst turnover (Scheme 1A).3 Using this strategy, we have
successfully achieved several challenging intermolecular
cascade condensations by forming a corresponding allylic
moiety. Through nitro group conversion, various functional
groups have been successfully installed at the C-1 position
including 1,2,3-triazole, dihydrofuran, and isooxazoline-N-
Scheme 1. β-Alkyl Nitroalkene: A Versatile Synthon
One interesting intermediate, which we observed during the
mechanistic investigation of previous reported allylic sulfona-
tion, is E (X = SO2Ar). We also proved that E could slowly
convert into allyl sulfone products under the reaction
condition. Although the exact mechanism for nitro-elimination
remained unclear, the result suggested that NO2 could serve as
a valid leaving group under oxidative conditions. More
importantly, the formation of E revealed an alternative reaction
pathway, benefiting our goal of achieving 1,3-difunctionaliza-
tion of β-alkyl nitroalkene. As proposed in Figure 1A,
isomerization of allylic nitro compound 1a′ is a well-known
Received: December 12, 2020
Published: January 13, 2021
https://dx.doi.org/10.1021/acs.orglett.0c04106
© 2021 American Chemical Society
Org. Lett. 2021, 23, 886−889
886

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Letter
a b
,
Table 1. Reaction Condition Screening
entry
reaction conditions varies from standard
yield of 3a (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
none
no TBAI
95
54
10
91
0
30
80
83
93
80
0
I2 as Lewis base
NaI as Lewis base
NaOAc as Lewis base
DTBP as oxidant
H2O2 as oxidant
m-CPBA as oxidant
Mn(OAc)3·H2O as oxidant
Cu(OAc)2·H2O as oxidant
DMF as solvent
toluene as solvent
at 60 °C
Figure 1. New strategy for nitroalkene dual functionalization.
0
57
0
process under basic conditions. In the presence of peroxide as
the oxidant, carbanion B can be oxidized to radical C. Sulfonyl
radical C-3 addition then yielded the intermediate E (path B).
E itself could serve as a valid precursor for 1,3-difuntionaliza-
tion of nitroalkene through the nitro-group functional group
transformation. Various efforts have been made to improve the
yield of E; however, no progress has been achieved due to the
high unitability of E. We are wondering if the application of
radical traps will help quench intermediate C and facilitate
further transformation (path A).8
at 45 °C
a
General reaction conditions: 1a (0.3 mmol, 1 equiv), TEMPO (0.6
mmol, 2 equiv), LB (0.06 mmol, 20 mol %), and oxidant (2 equiv) in
solvent (3.0 mL), open air. Isolated yield.
b
modest yield was observed (entry 2). Iodine anion was found
to be the optimal one. I2 led to a lower yield, which might be
due to the inactivity of I2 with TEMPO (entry 3). Another
peroxide reagent could also promote the reaction in good yield,
indicating the feasibility of allylic anion oxidation (entries 6−
8). Similarly, metal oxidants, such as Cu(OAc)2 and Mn-
(OAc)3, were also suitable for this transformation through a
single-electron oxidation process (entries 9 and 10). Other
solvents, such as toluene and DMF, gave poor yield of the
desired product (entries 11 and 12). MeCN was found to be
the optimal solvent. Accordingly, a high temperature (80 °C)
is necessary to accelerate the elimination process for the
reaction completion (entries 13 and 14). With the optimal
condition in hand, we then explored the substrate scope
(Scheme 2).
As shown in Scheme 2, β-aryl nitroalkenes with an aryl ring
containing either electron-withdrawing or electron-donating
group substituents are suitable for this transformation,
providing excellent yields (3a−3l). The position of sub-
stituents (o, m, or p) on aryl rings also has little impact on the
reaction performance. Notably, more electron-rich aromatic
rings, such as 3,4-dimethoxybenzene (3l) and naphthalene
(3m), also afforded the desired product in good yields,
suggesting that the mild radical oxidation selectively targets an
allylic anion over aromatic rings. Nitroalkene-bearing β-ethyl
groups (3o−3q) can also be tolerated, providing correspond-
ing ketone product in good yield. (Nitromethylene)-
cyclohexane derivetive (3o) gave modest yield, which might
be caused by the elimination of γ-C−H according to our
previously reported cases. We then further explored the scope
of TEMPO. 4-OH-substituted TEMPO compounds (4a−4e)
were tested for this reaction. The hydroxide group on TEMPO
is well-tolerated, without competing with hydroxyl addition
and allyic alcohol oxidation. The desired products were
obtained in excellent yield. With 4-OTs-substituted TEMPO
(4f, 4g), the decreased yield was observed; it might be because
OTs is a good leaving group. As a comparison, 4-OEt-
To investigate this idea, we first conducted the reaction
between nitroalkene 1a and sodium sulfinate (10 mol % of I2, 2
equiv of TBHP, DMSO, 80 °C, previously reported optimal
condition) in the presence of TEMPO as the radical trap.
Unfortunately, we did not observe TEMPO radical-trapped
nitroalkene-functionalized product formation nor the allylic
sulfone 2a (Figure 1B). This might be because TEMPO
quenched the formed sulfonic radial. Therefore, we later ran
the reaction without the addition of sodium sulfinate. To our
delight, we successfully isolated a new product in 30% yield, as
confirmed by X-ray crystallography as 3a (CCDC: 1984460).
This result proved our hypothesis on the feasibility of allylic
anion oxidation. Notably, NO2 elimination was also achieved
through an E1cB-type mechanism with hydroxyl addition.
Sequential fast TEMPO promoted allylic alcohol oxidation to
yield an aldehyde product.9 Although the yield was very low
(30%), this result was very promising as it confirmed our
proposed reaction path as a new direction for nitroalkene dual
functionalization. To optimize this reaction, various conditions
were screened, including Lewis base catalysts, alternative
oxidants, solvents, reaction temperatures, etc. We revealed that
the optimal condition uses 20 mol % of TBAI as the Lewis
base and 2 equiv of TBHP as the oxidant at 80 °C in MeCN.
The desired vinylic alkoxyamine 3a was prepared in 95%
isolated yield. To the best of our knowledge, this is the first
example of the successful combination of radical trapping and
nitro-elimination, which revealed a new reaction path to
further enhance the synthetic utility of β-alkyl nitroalkene
synthons. Screening results with some alternative conditions
are summarized in Table 1 (for more screening conditions, see
the Supporting Information).
As shown in Table 1, the Lewis base, which can promote the
fast isomerization from 1a to 1a′, was found to be crucial to
the reaction performance. Without the Lewis base, only
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https://dx.doi.org/10.1021/acs.orglett.0c04106
Org. Lett. 2021, 23, 886−889

Organic Letters
pubs.acs.org/OrgLett
Letter
a b
,
starting material, the pyrazole-bearing cyclohexene ring on the
4,5-position of 6 was obtained in 90% yield. This protocol
offered an alternative route to fast construction of this type of
pyrazole structure, which cannot be easily accessed using the
previously reported method.11 The reaction kinetic profile was
also conducted and confirmed that the fast equilibrium toward
1a′ through Lewis base catalysis is the key for further
transformation (Figure 2B).
Scheme 2. Substrate Scope
In conclusion, we report herein an alternative approach
toward β-alkyl nitroalkene functionalization. In the presence of
TEMPO under radical oxidation conditions, we can success-
fully achieve vinylic alkoxyamines with a high efficiency. Also,
this synthon contributes to the challenging pyrazole synthesis.
Further mechanistic studies and the synthetic application of
this transformation are the focus of ongoing investigations.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04106.
Experiment procedures, condition optimization, reaction
profile, X-ray single-crystal diffraction, and character-
ization for all products (PDF)
Accession Codes
a
General reaction conditions: 1a (0.3 mmol, 1 equiv), TEMPO (0.6
CCDC 1984460−1984461 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
mmol, 2 equiv), LB (0.06 mmol, 20 mol %), and oxidant (2 equiv) in
solvent (3.0 mL), open air. Isolated yield.
b
substituted TEMPO compounds (4h, 4i) lead to a higher yield
for this reaction. Notably, this result offered a potential
application by adopting TEMPO as a linkage between α,β-
unsaturated aldehyde and 4-functionalized TEMPO, which is
currently being investigated in our lab for its application.
To further explore the synthetic utility for obtained vinylic
alkoxyamines, we expected that 3a could serve a good 1,3-
dipolar synthon to construct interesting heterocyclic structures.
With this in mind, we conducted the reaction between 3a with
PhNHNH2 using TsOH as catalyst in MeOH at 80 °C (Figure
2A). As expected, 1,4-diphenyl-substituted pyrazole 5 was
detected in excellent yield (93%).10 In this case, TEMPO
serves as a good leaving group. Furthermore, with 3o as the
AUTHOR INFORMATION
■
Corresponding Authors
Yunfeng Chen − School of Chemistry and Environmental
Engineering, Wuhan Institute of Technology, Wuhan 430205,
P.R. China; orcid.org/0000-0002-6220-5015;
Email: yfchen@wit.edu.cn
Xiaodong Shi − Department of Chemistry, University of South
Florida, Tampa, Florida 33620, United States; orcid.org/
0000-0002-3189-1315; Email: xmshi@usf.edu
Authors
Ye Wang − School of Chemistry and Environmental
Engineering, Wuhan Institute of Technology, Wuhan 430205,
P.R. China
Lei Zheng − School of Chemistry and Environmental
Engineering, Wuhan Institute of Technology, Wuhan 430205,
P.R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04106
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21002076) and the Graduate Innovative Fund of
Wuhan Institute of Technology (CX2019166).
Figure 2. Derivatives and reaction kinetics.
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