N2H4-H2O Enabled Umpolung Cyclization of o-Nitro Chalcones for the Construction of Quinoline N-Oxides

Article abstract of DOI:10.1021/acs.orglett.0c04162

Umpolung is a unique strategy which converts the property of an atom into the opposite one. An efficient and general method for the construction of quinoline N-oxides via umpolung of carbonyl groups was developed from ortho-nitro chalcones and hydrazine i

Full text of DOI:10.1021/acs.orglett.0c04162

pubs.acs.org/OrgLett
Letter
N2H4−H2O Enabled Umpolung Cyclization of o‑Nitro Chalcones for
the Construction of Quinoline N‑Oxides
Guan Zhang, Kai Yang, Shihui Wang, Qiang Feng, and Qiuling Song*
Cite This: Org. Lett. 2021, 23, 595−600
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ABSTRACT: Umpolung is a unique strategy which converts the property of an atom into the opposite one. An efficient and general
method for the construction of quinoline N-oxides via umpolung of carbonyl groups was developed from ortho-nitro chalcones and
hydrazine in basic conditions. The strategy is transition-metal free and has good functional group tolerance, environmental
friendliness, as well as mild reaction conditions with nitrogen gas as the byproduct.
N-Oxide compounds are an important class of heterocyclic
compounds which are widely found in natural products and
bioactive molecules.1 Among them, quinoline N-oxides have
unique properties and widespread applications as organo-
catalysts,2 the directing groups in C−H activations,3 as well as
the core skeletons of alkaloid Aurachins A;4 in addition, they
are also very important oxidants in gold-catalyzed reactions
(Figure 1).5
with sensitive functional groups (Scheme 1Ai).6 For the
second one, the nitro group of 2-nitrochalcone is reduced to
hydroxylamine which further cyclizes to obtain quinoline N-
oxide under a reductive system (Scheme 1Aii).7 For the third
one, the nitro group is attacked by an in situ generated
carbanion to form quinoline N-oxides under the redox-neutral
conditions (Scheme 1Aii),8 which lacks broad substrate scope.
Given the importance of quinoline N-oxides, it becomes highly
desirable to develop a general and efficient strategy to access
versatile quinoline N-oxides.
The carbonyl group has been extensively studied in
contemporary organic synthesis. The positively polarized
carbonyl carbon is a versatile reaction site for various
nucleophilic reagents, and such nucleophilic attacks can further
derive many other chemical reactions. Umpolung of a carbonyl
group to a nucleophilic carbon atom has greatly expanded the
diversity of carbonyl-compound-involved transformations. For
example, the reaction of aldehydes with 1,3-dithiol can lead to
an electrophilic thioacetal,9 which could consequently
deprotonate with organolithium reagents to form a carbanion.
Benzoin condensation is another typical umpolung reaction in
which CN− attacks the carbonyl group of aldehyde, and
subsequent hydrogen transfer results in a nucleophilic
intermediate which further attacks another aldehyde to lead
to an α-hydroxy ketone.10 Later, the N-heterocyclic carbene
(NHC) was developed to achieve a similar reaction.11 In 2015,
Figure 1. Selected examples of important compounds containing
quinoline N-oxides.
Despite their importance in chemistry, interestingly, efficient
methods for the synthesis of quinoline N-oxides are rather rare.
There are three main synthetic strategies for the construction
of quinoline N-oxides (Scheme 1A): (1) oxidation of
quinolines;6 (2) reductive cyclization of 2-nitrochalcones;7
and (3) carbanion and nitro cyclization under redox-neutral
conditions.8 The first one needs elevated temperature under
oxidative conditions; therefore, this strategy is not compatible
Received: December 16, 2020
Published: December 30, 2020
https://dx.doi.org/10.1021/acs.orglett.0c04162
© 2020 American Chemical Society
Org. Lett. 2021, 23, 595−600
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to a methylene moiety.13 The mechanism also reflected the
polarity reversal of the carbonyl group. Li and co-workers
reported a Rh-catalyzed umpolung reaction with aldehydes as
carbanion equivalents to react with ketones to render tertiary
alcohols. Subsequently, the same group used these masked
alkyl carbanions to achieve cross-coupling reactions with aryl
ethers, aryl halides, etc.14 However, the efficiency of the
aforementioned transformations is also often predicated on
expensive and toxic metals. Herein, we conceived a transition-
metal-free strategy by umpolung reaction of the carbonyl group
(Scheme 1B): (1) hydrazone is formed between hydrazine and
the carbonyl group in basic conditions, and (2) after the
deprotonation and the double-bond migration, a carbanion
results, which intramolecularly attacks the nitro group,
eventually obtaining quinoline N-oxide. This reaction features
mildness, environmental benignity, good functional group
tolerability, broad substrate scope, as well as scalability and
would provide an efficient and general strategy for the
construction of 2-substituted quinoline N-oxides.
Scheme 1. Quinoline N-Oxide Synthesis
Under our conception, the general potential of the
envisioned process was first investigated on model substrate
2-nitrochalcone (1a) with hydrazine hydrate (2a) in Table 1.
Initially, NaHCO3 (1 equiv) was used as the base to examine
the reaction in the EtOH. To our delight, the expected product
3aa was obtained albeit in low yield (entry 1). Base screening
suggested that NaOH was the optimal one (entries 2−4). The
NaOH was prepared as an aqueous solution (entries 4−14).
Interestingly, the reaction went smoothly at 70 °C to produce
the desired cyclic product 3aa in 50% yield (entry 6). Solvent
screening suggested that the protic solvents had poor
efficiency, while the ether solvents were superior ones.
Among them, THF was the optimal one to deliver 3aa in
70% yield (entry 12). We were rather happy to find that after
decreasing the amount of base, reaction time, as well as the
amount of hydrazine hydrate the yield of 2-phenylquinoline 1-
the Deng group reported a novel strategy for the synthesis of
chiral amines based on the umpolung reaction of aldehydes
with benzylamines, followed by nucleophilic addition of the in
situ generated aza-allyl anion to the α,β-unsaturated systems.12
The Wolff−Kishner reduction is a classic reaction which
involves a deoxygenation process of the carbonyl group to lead
a
Table 1. Development of Optimized Conditions for 2-Phenylquinoline N-Oxide Formation
c
entry
base (equiv)
solvent (mL)
temp (°C)
time (h)
N2H4−H2O (equiv)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
NaHCO3 (1)
K3PO4 (1)
K2CO3 (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (0.5)
EtOH (2)
EtOH (2)
EtOH (2)
EtOH (2)
EtOH (2)
EtOH (2)
EtOH (2)
MeOH (1)
MeCN (1)
1,4-dioxane (1)
Toluene (1)
THF (1)
90
90
90
90
80
70
60
70
70
70
70
70
70
70
5
5
5
5
5
5
5
5
5
5
5
5
2
2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2.5
15
23
13
42
48
50
46
10
n.r.
66
25
70
72
b
THF (1)
THF (1)
d
94 (85)
a
Reaction conditions: 1a (0.2 mmoL), 2a (0.5 mmoL), and NaOH (0.1 mmoL) in THF (1 mL) at 70 °C heating under an oil bath for 2 h, under
b
c
nitrogen. NaOH is sodium hydroxide in water with 17 mmoL/mL. Yield determined by 1H NMR analysis using dibromomethane as the internal
standard. Isolated yield. THF = tetrahydrofuran, n.r. = no reaction.
d
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oxide (3aa) was subsequently increased to 94% yield (entry
14), which eventually was proven to be the best reaction
condition.
With the optimal conditions in hands, the substrate scope of
2-nitrochalcones was investigated for this umpolung reaction
(Scheme 2). First, different substituents on Ar1 rings were
substituents on the Ar2 ring were also investigated. Once again,
halogen groups, as well as electron-deficient and electron-rich
groups, were all compatible, and the corresponding desired
quinoline N-oxides (3ka−3sa) were obtained in decent yields.
The 4-phenyl substrate could also render the target product
3na in modest yield. In addition, when the Ar2 ring was
replaced with a naphthalene ring, both 1-naphthalene and 2-
naphthalene were well tolerated, and the corresponding
products 3ta and 3ua were obtained in good yields. Of note,
when Ar2 is a conjugated olefin which is derived from the violet
ketone, the product 3va was obtained in a medium yield as
well.
a
Scheme 2. Substrate Scope of 2-Nitrochalcones
We next surveyed the scope of α,β-unsaturated carbonyl
compounds whose R group was heteroaromatic rings or alkyl
groups (Scheme 3). To our delight, this transformation has
Scheme 3. Substrate Scope of 2-Heteroaromatic or Alkyl-
a
Substituted Quinoline N-Oxides
a
Reaction conditions: 1a (0.2 mmoL), 2a (0.5 mmoL), NaOH (0.1
mmoL), in THF (1 mL) at 70 °C heating under an oil bath for 2 h,
under nitrogen.
a
Reaction conditions: 4 (0.2 mmoL), 2a (0.5 mmoL), NaOH (0.1
mmoL), in THF (1 mL) at 70 °C heating under an oil bath for 2 h,
under nitrogen atmosphere.
explored (3ba−3ia). Substrates bearing either electron-
deficient or electron-rich substituents at the different positions
of Ar1 rings all afforded comparable yields. Under the standard
conditions, the halogen (−Cl, −Br, and −F) groups were well
compatible, and the position of the substituent did not have
much effect on the reaction. When 2-nitrochalcone was
substituted with a strong electron-withdrawing group like the
trifluoromethyl group on the aromatic ring, the corresponding
product 3fa was obtained in excellent yield. When the
substituent on the Ar1 ring was replaced with an electron-
rich group, the yield of the reaction did not decrease
significantly (3ga−3ia). A sterically hindered substrate could
also afford a preferable yield (3ja). Subsequently, the different
very good substrate scope. In addition to chalcones in which an
aromatic substituent was introduced to the 2-position of the
final products, heteroaromatic rings were also compatible
under the standard conditions, rendering the corresponding 2-
heteroaromatic-substituted quinoline N-oxides in moderate to
excellent yields (5ba−5fa). Moreover, 2-alkyl-substituted
quinoline N-oxides could also be smoothly afforded (like
adamantane, cyclopropane, and norbornene and so on) (5ga−
5la). The structure of 5ha was unambiguously demonstrated
by X-ray crystallographic analysis. The derivative of the drug
molecule pregnenolone was also a competent substrate under
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this mild condition (5ja), providing the possibility of
discovering new bioactive compounds.
To further demonstrate the practicality of this trans-
formation, a 10 mmol scale reaction smoothly proceeded,
and the corresponding quionline N-oxide 3aa was obtained in
78% yield without significant loss of efficiency (Scheme 4A). In
reaction of 10 under basic conditions and found that no
reaction occurred, which further suggested that compound 10
was not the intermediate for this transformation (Scheme 4F).
On the basis of our observations as well as the reported
literature,12−14,15 a tentative mechanism is proposed (Scheme
5): first, o-nitrochalcone 1a reacts with hydrazine 2a to form
Scheme 4. Large-Scale Synthesis and Mechanistic
Experiments
Scheme 5. Proposed Mechanism
order to thoroughly understand the mechanism of this
reaction, several control experiments were performed. As we
all know, hydrazine is a reductant; however, when nitro-
benzene 6 was subjected to our standard reaction conditions,
no reductive products were ever detected (Scheme 4B). This
result indicated that hydrazine could not be directly reduced
into a nitro group in our system. In addition, we found that 1-
naphthalene hydrazine (7) could also promote this reaction to
lead to the formation of naphthalene (8) in 51% yield with
25% of desired product 3aa (Scheme 4C). Inspired by Deng’s
work, we tried other reagents that could promote the polarity
reversal of carbonyl groups.12 When benzylamine (9) was
employed in the standard conditions, the quinoline N-oxide
3aa was obtained in a trace amount (Scheme 4D). The result
further verified that the reaction between N2H4−H2O and the
carbonyl group to hydrazone should be the key step for this
umpolung reaction. We tried to isolate the intermediate
hydrazone; however, the reaction between the hydrazone and
the olefin led to five-membered ring 10 in 90% yield, indicating
that the hydrazone is more active to react with olefin than the
nitro group (Scheme 4E). We further attempted to carry out
hydrazone A in situ, and the deprotonation of A in basic
conditions leads to B which quickly tautomerizes into
canbanion C, the umpolung reaction of the carbonyl group.
Carbanion C further intramolecularly attacks the nitro group
to deliver intermediate E. There is also a possible electrocyclic
ring-closure path via intermediate F. When hydrazine is used,
intermediate E undergoes proton transfer to obtain inter-
mediate G which further renders quinoline N-oxide 3aa after
releasing nitrogen gas and hydroxide. When 1-naphthalene
hydrazine is used instead, the quinoline N-oxide 3aa is
eventually obtained in basic conditions along with the
generation of the azo compound I (this process could also
be called [1,2]-sigmatropic rearrangement); of note, I is
unstable, which further decomposes into naphthalene along-
side one molecule nitrogen.16 The above control experiment in
Scheme 4C verified this process. In addition, the intermediate
G may also undergo homolysis through the intermediate J to
obtain radicals K and L. The radical K undergoes the release of
nitrogen, and hydrogen transfers from THF to form
naphthalene (8). Radical L is reduced and dehydroxylated to
obtain product 3aa. It is worth mentioning that HO− would be
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generated during the reaction, so the reaction does not require
an equivalent amount of base to obtain a high-yield product
(Table 1, entry 14).
We also thank the Instrumental Analysis Center of Huaqiao
University for analysis support. G. Zhang thanks the
Subsidized Project for Cultivating Postgraduates Innovative
Ability in Scientific Research of Huaqiao University.
In conclusion, we have developed a hydrazine-promoted
umpolung reaction of carbonyl groups under transition-metal-
free conditions, which undergoes intramolecular nucleophilic
cyclization to lead to 2-substituted quinoline N-oxides. This
reaction features a broad substrate scope, good functional
group tolerance, as well as novel mechanism, which might
provide more tactics for umpolung reaction of carbonyl groups
and nourish carbonyl chemistry.
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Experimental procedures and spectral data for all new
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AUTHOR INFORMATION
Corresponding Author
■
Qiuling Song − Institute of Next Generation Matter
Transformation, College of Chemical Engineering, College of
Material Sciences Engineering at Huaqiao University,
Xiamen, Fujian 361021, P. R. China; College of Chemistry,
Fuzhou University, Fuzhou 350116, P. R. China;
orcid.org/0000-0002-9836-8860; Email: qsong@
hqu.edu.cn
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Authors
Guan Zhang − Institute of Next Generation Matter
Transformation, College of Chemical Engineering, College of
Material Sciences Engineering at Huaqiao University,
Xiamen, Fujian 361021, P. R. China
Kai Yang − College of Chemistry, Fuzhou University, Fuzhou
350116, P. R. China
Shihui Wang − Institute of Next Generation Matter
Transformation, College of Chemical Engineering, College of
Material Sciences Engineering at Huaqiao University,
Xiamen, Fujian 361021, P. R. China
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the National Natural Science
Foundation (21772046, 2193103) is gratefully acknowledged.
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