Highly Regioselective and Chemoselective [3 + 3] Annulation of Enaminones with ortho-Fluoronitrobenzenenes: Divergent Synthesis of Aposafranones and Their N-Oxides

Article abstract of DOI:10.1021/acs.orglett.1c00710

A base-promoted unprecedented strategy for the regioselective and chemoselective divergent synthesis of highly functionalized aposafranones and their N-oxides has been developed from the [3 + 3] annulation of enaminones with o-fluoronitrobenzenenes. This novel synthetic strategy offers an alternative method for the construction of aposafranones and their N-oxides are meaningful in the fields of both biology and organic synthesis. The established protocol explores the annulation scope of enaminones, and it expands the application of nitro-based cyclization.

Full text of DOI:10.1021/acs.orglett.1c00710

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Letter
Highly Regioselective and Chemoselective [3 + 3] Annulation of
Enaminones with ortho-Fluoronitrobenzenenes: Divergent
Synthesis of Aposafranones and Their N‑Oxides
Xue-Bing Chen,* Shun-Tao Huang, Jie Li, Qi Yang, Li Yang, and Fuchao Yu*
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ABSTRACT: A base-promoted unprecedented strategy for the
regioselective and chemoselective divergent synthesis of highly
functionalized aposafranones and their N-oxides has been developed
from the [3 + 3] annulation of enaminones with o-fluoronitrobenze-
nenes. This novel synthetic strategy offers an alternative method for
the construction of aposafranones and their N-oxides are meaningful
in the fields of both biology and organic synthesis. The established
protocol explores the annulation scope of enaminones, and it expands
the application of nitro-based cyclization.
largely unexplored, and this area of research is still in its
infancy, especially pertaining to aposafranone N-oxides.8 Thus,
some synthetic methods for aposafranones construction have
been developed that involve acid-catalyzed annulation of o-
phenylenediamines with benzoquinones,7,8a,9a FeCl3-catalyzed
intramolecular of o-phenylenediamines,9b and multistep
reaction from o-fluoronitrobenzenenes (Scheme 1a).9c These
reactions often suffer from harsh reaction conditions, low
reaction efficiency, and tedious workup procedures. Therefore,
the development of new synthetic methods to construct these
compounds remains a high-value achievement.
Enaminones, which is a class of unique structures possessing
both enamine and ketene functions, have emerged as versatile
synthons for the construction of appealing and valuable
molecules, because of their high intrinsic reactivity.10 Despite
great progress in enaminone chemistry, some challenges still
exist and must be addressed. These include the issue of the
regioselectivity and/or chemoselectivity in enaminone chem-
istry, as well as the C(sp3)−H bond of the structure of
enaminones involved in specific transformations. Indeed, the
annulation of enaminones in previous studies has been based
on bis-nucleophilic sites (C3 and N1) for accessing various
heterocyclic compounds.11 Nevertheless, to the best of our
knowledge, no examples involving annulation of enaminones
henazines are an important polycyclic heterocyclic motif
1,2
Pfound in a variety of natural products,
bioactive
molecules,1,2a,3 and organic functional materials (e.g., solar
cells, photosensitizers, and photocatalysts).4 There are more
than 100 identified derivatives of phenazines in nature and
over 6000 synthesized compounds.1 Among them, phenazi-
nones and phenazine N-oxides have received significant
attention, because of their broad biological activities and
their enhanced utility in chemical biology (Figure 1).1,2a,5,6
One of the simplest phenazinones is aposafranone, which was
first synthesized in 1896 by Kehrmann et al.7 However, in
comparison with other phenazines, the strategies for the
synthesis of aposafranone and its analogues have remained
Received: March 1, 2021
Published: April 1, 2021
Figure 1. Representative biologically active phenazinone and their N-
oxide derivatives.
https://doi.org/10.1021/acs.orglett.1c00710
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3032−3037
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Scheme 1. Synthetic Methods of Phenazinones and
Annulation of Enaminones
Table 1. Optimization of Conditions for Aposafranone
a
Formation
temperature, T
(°C)
time
(h)
yield
c
b
entry
solvent
MeOH
CH2Cl2
EtOH
DMSO
DMF
MeCN
PhMe
1,4-dioxane Cs2CO3
additive
(%)
d
1
2
3
4
5
6
7
8
9
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
rt
rt
rt
rt
rt
rt
rt
rt
60
80
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
60
rt
rt
rt
4
4
4
12
12
4
NR
NR
NR
d
d
65
60
NR (40)
NR (36)
NR (41)
49
40
26
57
43
NR
NR
NR
55
e
e
e
4
4
DMSO
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Et3N
0.5
0.5
12
12
6
12
12
12
12
4
10 DMSO
f
11
12
13
DMSO
DMSO
DMSO
g
h
14 DMSO
15 DMSO
16 DMSO
17 DMSO
18 DMSO
19 DMSO
20 DMSO
21 DMSO
22 DMSO
23 DMSO
24 DMSO
piperidine
DBU
K2CO3
KOH
NaH
45
28
4
t-BuOK
P(OEt)3
TsOH
TFA
12
12
12
12
12
62
NR
d
NR
NR
NR
KHSO4
a
The reaction was performed with 1a (0.5 mmol), 2a (0.6 mmol) and
the solvent (3 mL). In this table, the abbreviation rt denotes room
temperature, and the abbreviation NR represent no reaction.
from the weak nucleophilic site C5 [including the C(sp3)−H
bond] with N1 have been reported to date, especially when the
strongest nucleophilic site C3 is not involved in the reaction
(Scheme 1b).
b
d
f
c
Additive (0.6 mmol). Isolated yields based on enaminone 1a.
e
Room temperature to reflux. The reaction temperature at 60 °C.
g
h
Cs2CO3 (0.25 mmol). Cs2CO3 (0.5 mmol). Cs2CO3 (1.0 mmol).
Following our continuous interest in the annulation of
enaminones,12 we herein report an unexpected [3 + 3]
annulation of enaminones with o-fluoronitrobenzenenes for
substrate-controlled divergent synthesis of aposafranones and
their N-oxides, and achieved regioselective and chemoselective
annulation of enaminones from the weak nucleophilic site C5
with direct participation of the nitro group in the annulation
reaction. The construction of aposafranones proceeded via the
formation of the first C−N bond through the addition of C5
and the nitro group, rather than the nucleophilic reaction
(SNAr) of N1 and o-fluoronitrobenzenenes.
We first investigated the annulation reaction employing
enaminone 1a and o-fluoronitrobenzenene 2a as model
substrates for optimization of the reaction conditions (Table
1). Initially, Cs2CO3 was used as the base to examine the
effects of temperature and solvent. The desired product 3a was
not obtained when the reaction was performed in methanol,
DCE, or ethanol at either room temperature or in reflux for 4 h
(Table 1, entries 1−3). Nevertheless, 3a was obtained in an
isolated yield of 65% within 12 h at room temperature in
DMSO (Table 1, entry 4). To improve the synthetic efficiency,
a variety of solvents including DMF, MeCN, toluene, and 1,4-
dioxane were evaluated. Among them, MeCN, toluene, and
1,4-dioxane failed to yield 3a at room temperature. However,
increasing the reaction temperature to 60 °C resulted in yields
of 40%, 36%, and 41%, respectively. (Table 1, entries 6−8).
The solvent DMF provided good solubility and resulted in
product 3a in 60% isolation yield at room temperature (Table
1, entry 5). From Table 1, it is apparent that DMSO was an
appropriate solvent. It was surprising that increasing the
reaction temperature to 60 °C and 80 °C reduced the yield of
3a to 49% and 40%, respectively (Table 1, entries 9 and 10).
The reaction was also sensitive to the equivalents of base used.
The reaction gave a lower yield of 3a either decreasing the
amount of Cs2CO3 to 0.5, and 1.0 equiv (Table 1, entries 11
and 12), or increasing the amount to 2.0 equiv (Table 1, entry
13). With 0.5 or 1.0 equiv of Cs2CO3 unreacted enaminone 1a
was observed after 12 h, while with 2.0 equiv of Cs2CO3, the
reaction mixture became complex after just 6 h. Next, in the
DMSO at room temperature, various inorganic and organic
bases were screened, including Et3N, piperidine, KOH, NaH,
K2CO3, and t-BuOK. The resulting data indicated that the
inorganic bases imposed some effect on the reaction (Table 1,
entries 17−20), and that organic bases failed to catalyze the
reaction (Table 1, entries 14−16). We also investigated the
catalytic activity of acidic (TsOH, TFA, and KHSO4) and
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phosphine additives P(OEt)3 under the same reaction
conditions, but the results are not satisfactory for these cases
(Table 1, entries 21−24). Consequently, it could be concluded
that the best reaction conditions for the construction of
aposafranone 3a were Cs2CO3 as the base in DMSO at room
temperature.
Scheme 3. Substrate Scope of 4a
With the optimal conditions in hand, we then extended the
reaction to a range of readily available enaminones 1 (Scheme
2). First, we tested the substrate scope of N-substituted 3-
a
Scheme 2. Aposafranones 3 Synthesis
However, when the reaction temperature was enhanced at 40
°C, we found that the reaction completed quickly and obtained
the desirable aposafranone N-oxide 5a with complete
regiocontrol in low yield (7%).
To increase the yield, various reaction conditions were
screened. Initially, we continued to enhance the temperature of
the reaction from 50 °C to 110 °C, the yield increased from
20% to 37%, accompanied by a reduction in the yield of 6 from
35% to 20%. Next, we controlled the sequence of initial
substrate addition, with enaminone 4a and Cs2CO3 added first
and stirred for 1 h at 110 °C, and then 2,6-difluoronitro-
benzene 2b was added to the mixture. Excitingly, this manner
led to the formation of aposafranone N-oxides 5a at a 47%
yield with a trace amount of side product 6 (Scheme 3B).
Further increasing the reaction temperature to 120 °C and 140
°C, the desired product 5a gave yields of 47% and 44%,
respectively. These results therefore showed that the best
reaction temperature was 110 °C. According to the results
shown in Table 1, the better solvents (DMF, CH3CN, 1,4-
dioxane, toluene) and bases (K2CO3, KOH) were screened
next at 110 °C. The results suggest that DMSO and Cs2CO3
continued to be the optimal solvent and base. Thus, it can be
concluded that the optimal reaction conditions for the
preparation of aposafranone N-oxides were 1.2 equiv Cs2CO3
as the base at 110 °C in DMSO.
Under these optimal reaction conditions, we turned our
attention to investigating the cascade reaction for preparing the
other target molecules 5, and the series of aposafranone N-
oxides 5a−5r were synthesized with moderate yields (Scheme
4). Similar to the results of Scheme 2, the reaction was
tolerated when 4 aromatic rings bearing an electron-with-
drawing or electron-deficient group at different positions and
afforded comparable yields. It was observed that the
substituents (R′ = F) on substrates (2) had some influence
on the yields of 5, affording lower yields than those with no
substitutions.
a
The reaction was performed with 1 (0.5 mmol), 2 (0.6 mmol), and
Cs2CO3 (0.6 mmol), in DMSO (3 mL) at room temperature for
8−12 h; isolated yields are based on enaminones 1. One mmol scale.
b
aminocyclohex-2-enonephenyls 1a-1j. To our delight, sub-
strates bearing either electron-rich or electron deficient
substituents, such as halogen, methyl and methoxy, at different
positions (meta-, ortho-, para-) of the rings all generated
corresponding aposafranone products 3a−3j with moderate to
good yields. The results indicated that the electronic effects
and steric hindrance did not have much impact on the
reaction. Subsequently, we also evaluated the scope of the o-
fluoronitrobenzenenes. The 2,6-difluoronitrobenzene 2b was
used as the substrate under the optimized conditions and also
afforded the target products 3j, 3k, and 3l at yields of 46%,
45%, and 53%, respectively. Disappointingly, the target
molecule 3 was difficult to purify. In the process of column
chromatography, part of the products will be adsorbed on the
silica gel, which further converted to some larger polar and
difficult-separated materials, and consequently, the yield of 3
was only moderate.
We next extended the scope of the reaction by using N-aryl
3-amino-5,5-dimethylcyclohex-2-enones 4. Under the optimal
conditions in Table 1, we first tested the reaction of 3-amino-
5,5-dimethylcyclohex-2-enone 4a with 2,6-difluoronitroben-
zene 2b. Disappointingly, this reaction only produced N-aryl
enaminone 6 with 41% yield, because of the larger steric
hindrance on the C5-position of substrate 4 (Scheme 3A).
The chemical structures of 3 and 5 were identified from
1
their IR, H NMR, 13C NMR, and HRMS spectra, and were
supported by single crystal X-ray diffraction analysis of
compound 5l (Figure 2).
To support the proposed mechanism, intermediate 6 was
employed under the standard conditions; however, the
aposafranone N-oxides 5a was not generated and no other
transformation occurred in this reaction (Scheme 5). The
results of Schemes 5 and 3B verified that the key step for this
reaction should be the formation of the enamine-enol oxygen
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a
Scheme 4. Aposafranones N-oxides 5 Synthesis
Scheme 5. Mechanistic Experiments
Scheme 6. Proposed Mechanism
a sequential enamine−imine/carbon anion−enol oxygen anion
tautomerization to give intermediate B. Next, intermediate B
undergoes enamine−imine tautomerization to form C.
Intermediate C further attacks the nitro group of o-
fluoronitrobenzene, followed by dehydration to deliver
intermediate E. It is most likely that two possible paths exist
on the way from E to 5. In path a, intramolecular SNAr of the
o-fluorine of the aryl group generates aposafranone N-oxides 5
with the elimination of HF by attack of the −NH group. In
path b, the intermediate F may undergo intramolecular 6π
electrocyclic ring closure to obtain 5. Other aposafranone
products 3 could also be obtained by losing one molecule of
water.
In summary, we have developed a cesium carbonate-
promoted method for regioselective and chemoselective
construction of two libraries of highly functionalized
aposafranones and their N-oxides, which explores the
application of Cadogan-type cyclization. This is the first
example of the annulation of enaminones to use the weak
nucleophilic site C5 [including the C(sp3)−H bond] and N1
to open the reaction scope of N-substituted enaminones.
Therefore, we anticipate that this protocol will be of interest
for both the organic and medicinal chemistry communities.
a
The reaction was performed with 1 (0.5 mmol), 2 (0.6 mmol), and
Cs2CO3 (0.6 mmol), in DMSO (3 mL) at 110 °C for 3−4 h; isolated
b
yields are based on enaminones 4. One mmol scale.
ASSOCIATED CONTENT
* Supporting Information
■
sı
Figure 2. X-ray crystal structures of 5l; ellipsoids are drawn at a 30%
probability level.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00710.
Spectroscopic and analytical data as well as the original
copy of 1H and 13C NMR spectra of all new compounds
(PDF)
anion intermediate by the base-abstracted −NH proton of
enaminone.
Based on the above results and the reported literature,13
a
Accession Codes
plausible mechanism for this reaction is proposed in Scheme 6.
First, the −NH proton of enaminone was abstracted by the
base Cs2CO3 leading to intermediate A, which then undergoes
CCDC 2064774 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
3035
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AUTHOR INFORMATION
Corresponding Authors
■
Xue-Bing Chen − College of Science, Honghe University,
Mengzi 661199, Yunnan, China; orcid.org/0000-0002-
1936-1274; Phone: +86 873 3649923;
Email: orangekaka@126.com
Fuchao Yu − Faculty of Life Science and Technology, Kunming
University of Science and Technology, Kunming 650504,
People’s Republic of China; orcid.org/0000-0001-5557-
3824; Phone: +86 873 3649923; Email: yufuchao05@
126.com
́
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F.; Nyga, A.; Stachelek, P.; Tohnai, N.; de Silva, P.; Data, P.; Takeda,
Y.; Minakata, S. Thermally activated delayed fluorescent donor−
acceptor−donor−acceptor π-conjugated macrocycle for organic light-
emitting diodes. J. Am. Chem. Soc. 2020, 142, 1482−1491. (f) Chun,
S.; Chung, Y. K. Transition-metal-free poly(thiazolium)iodide/1,8-
diazabicyclo[5.4.0]undec-7-ene/phenazine-catalyzed esterification of
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Authors
Shun-Tao Huang − College of Science, Honghe University,
Mengzi 661199, Yunnan, China
Jie Li − College of Science, Honghe University, Mengzi 661199,
Yunnan, China
Qi Yang − College of Science, Honghe University, Mengzi
661199, Yunnan, China
Li Yang − College of Science, Honghe University, Mengzi
661199, Yunnan, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00710
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (No. 21961018) and Program for
Innovative Research Team (in Science and Technology) in
University of Yunnan Province.
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