From Surprising Solvothermal Reaction to Uncommon Zinc(II)-Catalyzed Aromatic C-H Activation Reaction for Direct Nitroquinoline Synthesis

Article abstract of DOI:10.1021/acs.inorgchem.7b00653

In this work, we first found a surprising solvothermal reaction for direct dinitration of quinoline derivative. To explore the application in direct nitroquinoline synthesis, this reaction was subsequently modified as an equivalent reaction in a Schlenk tube. More significantly, after a constant attempt, nitrated derivative was obtained in optimized condition with a zinc(II) sulfate catalyst, where some substrates with strong electron-withdrawing group were first nitrated by a directly catalyzed condition. This new zinc(II)-catalyzed aromatic C-H activation reaction is the first example of direct dinitration by a single catalyst, which will be a new facile and environmentally friendly strategy to access synthetically useful nitroquinoline derivative.

Full text of DOI:10.1021/acs.inorgchem.7b00653

Article
pubs.acs.org/IC
From Surprising Solvothermal Reaction to Uncommon
Zinc(II)-Catalyzed Aromatic C−H Activation Reaction for
Direct Nitroquinoline Synthesis
Yazhen Wang,† Feihu Yu,† Xiao Han,† Ming Li,† Yue Tong,† Jie Ding,*,† and Hongwei Hou*,†
†The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
S
* Supporting Information
ABSTRACT: In this work, we first found a surprising
solvothermal reaction for direct dinitration of quinoline
derivative. To explore the application in direct nitroquinoline
synthesis, this reaction was subsequently modified as an equiv-
alent reaction in a Schlenk tube. More significantly, after a
constant attempt, nitrated derivative was obtained in optimized
condition with a zinc(II) sulfate catalyst, where some sub-
strates with strong electron-withdrawing group were first
nitrated by a directly catalyzed condition. This new zinc(II)-
catalyzed aromatic C−H activation reaction is the first example
of direct dinitration by a single catalyst, which will be a new
facile and environmentally friendly strategy to access synthetically useful nitroquinoline derivative.
nitrated by a directly catalyzed condition. This new zinc(II)-
catalyzed aromatic C−H activation reaction is the first example
of direct dinitration by a single catalyst, which will be a new
cheap and environmentally friendly strategy to access syntheti-
cally useful nitroquinoline derivative, except for the noble metal
or valence-variable metal-catalyzed route that emerged recently.
INTRODUCTION
■
The development of synthetic quinoline derivative is of con-
siderable interest to many disciplines, including medicine,1,2 dye,3
catalyst,4 and material.5 Especially, nitroquinoline derivative is
one of the important intermediates for fine chemical with
versatile biological and pharmacological activities,6 while it is
also an important entity in synthesis to participate in different
useful transformations.7,8 Except for these, 5-nitroquinoline
derivative has been designed and synthesized as a potential pro-
drug system for the antibody-directed enzyme pro-drug therapy
(ADEPT) or gene-directed enzyme pro-drug therapy (GDEPT).9
More recently, nitroquinoline derivative was studied as the
fluorescent probe of cellular hypoxia.10
Indeed, because traditional direct nitration methods com-
monly use harsh conditions,11 such as strong acidic or strong
oxidative condition, it is foreseeable with imperfect functional
group tolerance as well as undesirable byproduct and acidic
waste. In recent years, great interest focused on more versatile
and greener approaches for aromatic nitro compounds.12,13
Among these, transition metal-catalyzed transformation is
one promising but indirect protocol, because of the neces-
sarily prefunctionalized substrate.14 Inspired by these early
researches, metal-catalyzed direct C−H nitration protocols
have emerged in recent years.15 Unlike many other aromatic
compounds, poor electrophilic substitution activity of quino-
line ring considerably hindered the direct nitration develop-
ment.16−19 Especially, the direct dinitration by a single catalyst
was never reported. Herein, we report that an astonishing direct
zinc(II)-catalyzed nitration protocol for quinoline derivative
was optimized by a surprising solvothermal reaction that
was first found by our group. Interestingly, in this case, some
substrates with strong electron-withdrawing group were first
EXPERIMENTAL SECTION
Materials. All the solvents and reagents were purchased from
commercial source without further purification.
■
Synthesis. The details were shown in Supporting Information.
Physical Measurements. IR spectra were measured as KBr pellets
using a Nicolet iS50 FT-IR spectrometer. Elemental analyses for
carbon, hydrogen, and nitrogen were performed on a FLASH EA 1112
1
analyzer. H NMR and 13C NMR spectra were recorded on a Bruker
AV 400 MHz spectrometer. Mass spectra (MS) were recorded on a
Bruker Esquire 3000 plus ion trap mass spectrometer (Bruker-Franzen
Analytik GmbH, Bremen, Germany). High-resolution mass spectrom-
etry was performed in electrospray ionization time-of-flight mode
using a Micromass Q-TOF Micro mass spectrometer.
The crystallographic data of 1 were collected on a Rigaku Saturn
724 CCD diffractometer with Mo Kα radiation (λ = 0.710 73 Å). The
crystallographic data of 1a, 5a, 13b, and 18 were collected on a Bruker
D8 VENTURE diffractometer with Mo Kα radiation (λ = 0.710 73 Å).
The data were corrected by Lorentz and polarization effects. Data
were corrected for absorption effects using the Multi-Scan method
(SADABS). The structures were solved by direct methods and refined
with a full-matrix least-squares technique based on F2 with the SHELXL-97
crystallographic software package. The data were corrected by Lorentz
and polarization effects. Absorption corrections were applied by
utilizing a numerical program. The structures were solved by direct
Received: March 12, 2017
© XXXX American Chemical Society
A
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a
Scheme 1. Screening of Several Ancillary Groups
a
Reaction condition: substrate (0.03 mmol), Zn(NO3)2 (0.2 mmol), HOAc (0.4 equiv, 0.012 mmol), CH3CN (10 mL), 130 °C in 72 h (isolated
yield).
a
Scheme 2. Selected Optimization of Reaction Conditions
a
Substrate (0.3 mmol), HOAc (0.4 equiv, 0.012 mmol), in 9 h (isolated yield).
methods and refined with a full-matrix least-squares technique based
on F2 with the SHELXL-97 crystallographic software package.
condition (Scheme 1, Table S6), 5,7-dinitration products of
8-substituted quinoline were obtained with relatively good yield.
Unexpectedly, the crystal 5c of product 5a linked with Zn(II)
ion was obtained (Figure S4 and Tables S7 and S8) by slow
evaporation after solvothermal procedure.
Although complicated after-treatment is commonly unneces-
sary in solvothermal reaction, the difficult optimization process
and relatively long reaction time will limit the application of this
procedure. In the search for more favorable protocols, when
solvothermal condition was replaced by reflux, no such nitra-
tion product was observed in best solvent CH3CN. Hence, we
chose Schlenk tube instead of autoclave to explore a new direct
dinitration reaction for 8-aminoquinoline derivative. At first,
when compound 2 was as the substrate, this solvothermal
reaction was fortunately alternated to a equivalent reaction in a
Schlenk tube at 130 °C in 9 h, where both 5,7-nitrated deriv-
ative 2a (yield: 48%) and 5-nitrated derivative 2b (yield: 24%)
RESULTS AND DISCUSSION
■
Initially, new compound N1,N4-di(quinolin-8-yl)terephthal
amide 1 (the full details of crystal structure are given in the
Supporting Information, Figure S1 and Tables S1 and S2)
was designed and synthesized as a quinoline-type ligand to
construct transition-metal coordination polymer. As follows, a
series of solvothermal procedures were essayed (Table S3);
however, only single crystal of 1a was obtained (the full details
are given in the Supporting Information, Figures S2 and S3
and Tables S4 and S5), which was an unexpected but aston-
ishing dinitrated product of substrate 1. On the basis of this,
we explored a series of solvothermal procedures in the early
essays for more information on this new dinitration reaction.
For excessive amounts of Zn in optimized weak organic acidic
B
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a
Scheme 3. Substrate Scope for the Preparation of Nitrated Derivatives
a
Substrate (0.03 mmol), ZnSO4·7H2O (0.006 mmol), acetic acid (0.4 equiv,0.012 mmol), TBN (8 equiv, 0.24 mmol) CH3CN (6 mL), 110 °C in
1
9 h (isolated yield). Yield calculated from H NMR spectra of mixed products 7a and 7d as well as that of mixed products 9a and 9d.
(Scheme 2, Table S9). However, it was ineffective below
Scheme 4. Control Experiments (I)
100 °C, where compound 2b was main product (Table S9,
entry 5). Similarly, the amount of solvent CH3CN was also
considered. When substrate 2 was 0.3 mmol, 6 mL of solvent
was the best choice. In additional, the amount of HOAc was
important for this dinitration reaction, where neither without
HOAc nor over 0.4 equiv of HOAc was suitable (Table S9,
entries 19−24). Significantly, even Zn(II) salt in catalytic
magnitude, the product 2a still was observed with a yield of 9%
(Scheme 2, entry 3), which might be further optimized to a
zinc(II)-catalyzed dinitration protocol. In contrast, under the
same condition except for the reaction temperature at 100 °C,
only product 2b was observed (entry 4).
Herein, a series of reaction condition alterations were
accomplished for the exploration of zinc(II)-catalyzed dinitra-
tion protocol, including nitro source, Zn(II) salt, acid, and
reaction temperature (Table S10). Interestingly, compound 2
was successfully converted into the desired product 2a in a
definitely good yield of 76% under the optimized condition
(Table S10, entry 14), where ZnSO4·7H2O was used instead of
Zn(NO3)2·6H2O with excessive tert-butyl nitrite (TBN) as
nitro source. At the same time, even increasing the amount of
substrate 2 to 3 mmol, the yield still maintained. As shown
in Scheme 3, under the same condition, a series of dinitrated
derivatives was prepared in relatively good yields.
were obtained. Subsequently, it was obvious that the higher
isolated yield was obtained by decreasing the reaction temperature
C
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the 5-nitrated (12b and 13b; the detail of crystal 13b shown in
Figure S5 and Tables S11 and S12) and 7-nitrated (13e)
products are obtained, which is also the first direct-nitration
example substrate with strong electron-withdrawing group.
From this information and the literature,17−19 we could
preliminarily construct a model of zinc(II)-catalyzed aromatic
C−H reaction mechanism. It might be a radical-controlled
reaction with an intermediate chelated by substrate and Zn(II)
ion, which was also indirectly supported by the found crystal
of 5c.
Scheme 5. Control Experiments (II)
To clarify the mechanism for this zinc(II)-catalyzed nitration,
the corresponding control experiments were performed.
At first, 1 equiv of TEMPO was used as a radical scavenger
in the reaction of 2 (Scheme 4). Thus, the nitration process was
distinctly suppressed. Similar results also were observed by the
reactions with radical scavenger BHT and BQ. Herein, it was
clear that the nitration reaction involved a radical process.
Second, when 2b was treated as a substrate in same nitration
condition to receive 2a with a yield of 32%. Hence, 2b or
7-nitrated product should be the intermediate for the forma-
tion of 2a from 2, where 2b possibly took precedence over
7-nitrated product. Subsequently, in N-methyl-N-(quinolin-8-
yl)benzamide 14 case, only the 5-nitrated product 14b was
found in low yield of 22%, indicating the necessity of free NH
unit. As shown in Scheme 5, when analogue 4 was used instead
of substrate 2, only the 5-nitrated product 4b was found in
intermediate yield of 49%. Furthermore, no nitrated product
existed in 8-aminoquinoline 3 or 8-hydroxyquinoline 5 case
as well as in substrate 15 case. Similarly, in the 5-chloro-8-
hydroxyquinoline 16 or its derivatives 17 and 18 (the details of
crystal 18 are shown in Figure S6 and Tables S13 and S14),
no nitrated product was present. These results described
above revealed that an intermediate chelated by substrate and
Zn(II) ion was necessary for this dinitration reaction, where
Especially, in such substrate 7, two dinitrated products 7a
and 7d (3,7-dinitrated) were observed, whereas only 5-nitrated
products were observed in substrates 6 and 8 cases, respec-
tively. Furthermore, similar phenomena were also present in
substrates 9 and 10 cases. Because of the different electron-
donating capability in furan or thiophene group, 9d was
generated in this zinc(II)-catalyzed reaction. Importantly, it is
the first report of the corresponding 3,7-dinitrated products 7d
and 9d obtained by a directly catalyzed nitration. More sig-
nificantly, although dinitrated product is absent in such
substrate 12 or 13 with strong electron-withdrawing group,
Scheme 6. Proposed Mechanism for This Catalyzed Nitration Reaction
D
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coordination capability of substrate with Zn(II) ion was neither
too strong nor too weak.
X-ray crystallographic information (CIF)
X-ray crystallographic information (CIF)
X-ray crystallographic information (CIF)
Herein, on the basis of the above facts, a suitable mechanism
for this catalyzed nitration reaction is proposed in Scheme 6.
In Step I, the first process is the coordination of substrate with
Zn(II) to form a chelated intermediate, while NO2· is generated
from TBN under thermal condition.17 Subsequently, NO2·
reacts with chelated intermediate at the C-5 or C-7 of quinoline
unit. Because of the largest pz orbital occupancy usually at C-5
of quinoline unit,19 the reaction between NO2· and C-5
possibly takes precedence over that between NO2· and C-7 in
this process. It mainly results in that when too strong or too
weak coordination capability of substrate with Zn(II) ion, only
the 5-nitrated product or no nitrated product is observed.
For instance, too strong coordination capability (like sub-
strates 4 and 15) is harmful to the removal of nitrated product,
while substrate (like substrates 3, 6, and 8) with weak coordi-
nation capability is difficult to generate the chelated inter-
mediate. Hence, in the 5-chloro-8-hydroxyquinoline 16 or
its derivatives 17 and 18, no nitrated product is a reasonable
phenomenon. At the third process is aromatization to provide
5-nitrated product Xb or 7-nitrated product Xe. The journey of
substrate with strong electron-withdrawing group (12 and 13)
will stop in this Step I. Comparing to substrate 12 with small
steric hindrance, the possibility of reaction between NO2· and
chelated intermediate at the C-7 of quinoline unit could be
enhanced in substrate 13. For most of other substrates, their
journey will continue to produce dinitrated target materials
(Step II, like Step I). Especially, on the one hand, in com-
parison with substrates 7 and 9, because of favorable steric
hindrance and electron-donating capability of acyl group,
7-nitrated product Xe might be the winner in Step I. On the
other hand, in Step II, the C-3 of quinoline unit that was
commonly passivated was activated to generate the uniquely
3,7-dinitrated products 7d and 9d by the similar reason.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: jieding@zzu.edu.cn. (J.D.)
*E-mail: houhongw@zzu.edu.cn. (H.H.)
ORCID
Hongwei Hou: 0000-0003-4762-0920
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
This work was financially supported by the National Natural
Science Foundation (Nos. 21371155, 21301157, and 21671174).
■
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CONCLUSION
■
Summarily, we first found a surprising solvothermal reaction
for direct dinitration of 8-aminoquinoline derivative. Inspired
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zinc(II) sulfate catalyst. More interestingly, some substrates
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The Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.inorgchem.7b00653.
Materials and instruments, synetheses and character-
ization data, molecular structures and packing diagrams,
crystal and structure refinement, selected bond lengths
and angles, optimization of reaction conditions, screening
of ancillary groups in solvothermal reaction, IR spectrum,
1H NMR and 13C NMR spectra (PDF)
CCDC1528057, 1447718, 1447717, 1528058, and
1477820 crystal data for 1, 1a, 5a, 13b, and 18 (CIF)
X-ray crystallographic information (CIF)
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DOI: 10.1021/acs.inorgchem.7b00653
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