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From N−H Nitration to Controllable Aromatic Mononitration and

Dinitration�The Discovery of a Versatile and Powerful
N‑Nitropyrazole Nitrating Reagent
Tao Yang, Xiaoqian Li, Shuang Deng, Xiaotian Qi, Hengjiang Cong, Hong-Gang Cheng, Liangwei Shi,*
Qianghui Zhou,* and Lin Zhuang*
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ABSTRACT: Nitroaromatics are tremendously valuable organic compounds with a long history of being used as pharmaceuticals,
agrochemicals, and explosives as well as vital intermediates to a wide variety of chemicals. Consequently, the exploration of aromatic
nitration has become an important endeavor in both academia and industry. Herein, we report the identification of a powerful
nitrating reagent, 5-methyl-1,3-dinitro-1H-pyrazole, from the N-nitro-type reagent library constructed using a practical N−H
nitration method. This nitrating reagent behaves as a controllable source of the nitronium ion, enabling mild and scalable nitration of
a broad range of (hetero)arenes with good functional group tolerance. Of note, our nitration method could be controlled by
manipulating the reaction conditions to furnish mononitrated or dinitrated product selectively. The value of this method in
medicinal chemistry has been well established by its efficient late-stage C−H nitration of complex biorelevant molecules. Density
functional theory (DFT) calculations and preliminary mechanistic studies reveal that the powerfulness and versatility of this nitrating
reagent are due to the synergistic “nitro effect” and “methyl effect”.
KEYWORDS: nitration, dinitration, nitrating reagent, nitroaromatics, nitro effect, methyl effect

N itroaromatics are tremendously valuable organic com-

pounds. On the one side, nitroaromatics have proven to
possess diversified practical values, with a long history of being
used as pharmaceuticals,1a,b agrochemicals,1c explosives,1d and
other function materials.1e,f On the other side, the nitro group
is regarded as one of the most versatile functional groups for
transformation,2a which enables nitroarenes the vital precur-
sors to a wide variety of chemicals, including nitrosoarenes,2b
anilines,2c−2e aromatic azo compounds,1e biaryls,2f,g hetero-
cycles,2h−2j etc. As a result, the exploration of aromatic
nitration has been a significant endeavor in both academia and
industry, culminating in the development of several impactful
nitration strategies (Figure 1A).3 The most influential and
widely used nitration strategy in both laboratory and industry
is electrophilic aromatic substitution (SEAr), with the “mixed
acids” protocol as the representative one, which requires the
use of concentrated nitric acid and another assisting reagent
(e.g., H2SO4, Tf2O or Ac2O) to generate the reactive
nitronium ion ([NO2+]).3a Other strategies include transition
© 2022 The Authors. Published by
American Chemical Society
2152
metal-catalyzed cross coupling4 or directed C−H activation5
with nitrites or nitrates, ipso-nitration of prefunctionalized
arenes6 (e.g., aryl boronic acids, aryl carboxylic acids, and aryl
metal species), oxidation of aryl azides7 or anilines,8 as well as
enzymatic,9 electrochemical,10 and photochemical nitrations.11
Despite their effectiveness, these methods suffer from certain
limitations, including (a) poor functional group tolerance due
to harsh reaction conditions (e.g., strong acids, strong oxidants
or high temperature), (b) the requirement of prefunctionaliza-
tion or directing group, and (c) adverse environmental impact.
Path-pointing efforts by the groups of Kauffman,12a Coburn,12b
Received: July 25, 2022
Revised: August 16, 2022
Accepted: August 17, 2022
Published: August 31, 2022
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Figure 1. Aromatics nitrations. TM: transition metal, DG: directing group, TBN: tert-butyl nitrite, CAN: ceric ammonium nitrate, and LA: Lewis
acid.
Olah,12c,d Pearson,12e Katayev,12f and recently by Wang11 et al.
paved another attractive way for arene nitration�using a N-
nitro-type reagent, such as N-nitrolactams, N-nitropyridine
salts, N-nitropyrazole, N-nitrosaccharin, and N-nitroimidazole
(Figure 1B). However, there are two challenges associated with
this approach. First is the lack of practical access to these N-
nitro-type reagents, which currently have to be prepared by
N−H nitration with either in situ-generated [NO2+] under
harsh conditions11,12a−f or a [•NO2] radical under electro-
catalysis.13 Second, most of the reported N-nitro-type reagents
displayed unsatisfied nitrating ability and a narrow substrate
scope.11,12a-e Therefore, a prerequisite to an efficient aromatic
nitration using N-nitro-type reagents could be the identi-
fication of a new generation of reagents with good reactivity,
which we envisaged could be realized through screening a
diversified reagent library specially designed and prepared
(Figure 1C). Herein, we report our work on both the
identification of a powerful nitrating reagent 5-methyl-1,3-
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dinitro-1H-pyrazole and the nitration of a broad range of
aromatics under mild conditions using this bench-stable
reagent (Figure 1D).
Our efforts started from developing a general protocol for
N−H nitration for the establishment of a diversified N-nitro
reagent library. After rational reaction design and careful
preliminary studies, we observed that the combination of tert-
butyl nitrite (TBN)14 and an additional oxidant ceric
ammonium nitrate (CAN)15 could promote N−H nitration
of pyrazoles (for details, see Table S1). Further optimization of
this attractive N−H nitration approach (for details, see Tables
S1−S4) led to the following optimal nitration conditions:
running the reaction in MeCN at 100 °C, with TBN as a
source of nitro and CAN and O2 as oxidants. Gratifyingly, as
shown in Table 1A, the N−H nitration of a variety of
substituted pyrazoles proceeded smoothly under the above
reaction conditions, furnishing the desired products 2a−s in
38−95% yields on a 3.0 mmol scale. Pyrazole substrates with
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Table 1. Establishment of N-Nitro-Type Reagent Library and Nitrating Activity Evaluationa

a
All reactions were performed on a 3.0 mmol scale unless otherwise noted. Isolated yields were reported. b2.0 equiv TBN. c1.0 mmol. dAll
reactions were performed on a 0.2 mmol scale and 1.2 equiv of 2 was applied. GC yields with biphenyl as an internal standard.

various substitutions were tolerated, including halides (2c−f),
cyano (2g), nitro (2h, 2i, 2o, 2p, and 2s), trifluoromethyl (2j),
ester (2k, 2q, 2r), and even free amide (2l). The reaction of
pyrazoles with C3 electron-donating substitution produced the
N-nitration products (2m and 2n) together with the C4
overnitrated products (2m′ and 2n′). Besides pyrazoles, other
N−H-containing heterocycles, such as pyrrolidinone (1t),
oxazolidin-2-one (1u), and benzotriazoles (1v−x) were also
suitable substrates for nitration. Interestingly, the N−H
nitration of substituted benzotriazoles afforded products as
an inseparable mixture of regioisomers in good yields (2w and
2x). Therefore, by following this N−H nitration protocol and
using inexpensive starting materials, we quickly established a
N-nitro reagent library with 28 members, laying the foundation
for the discovery of a new generation of nitrating reagents.
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We then evaluated the nitrating ability of these reagents
toward the model substrate naphthalene (3a) (Table 1B). The
reaction was performed in MeCN at 80 °C, with Cu(OTf)2 as
a Lewis acid catalyst.12d,16 During the systematic screening of
these nitrating reagents, an intriguing substituent effect on
their nitrating ability was observed. For instance, N-nitro
pyrazoles with electron-donating (2a, 2b) or weak electron-
withdrawing substituents (2e, 2f) afforded α-nitrated product
1-nitronaphthalene (4a) in 9−14% yields, with the exception
of 2d that furnished 4a in a 35% yield. In contrast, N-nitro
pyrazoles with a strong electron-withdrawing substitution (2g,
2k) possessed significantly enhanced nitrating reactivity, and
the corresponding yields of 4a increased to 30−64%. Notably,
the nitrating reactivity could be further tuned by additional
substitution on pyrazole. For instance, 2o and 2p derived from
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Table 2. Mononitration of (Hetero)arenes with 2oa,b

a
Standard conditions I: 3 (1.0 equiv), 2o (1.2−1.5 equiv), Yb(OTf)3 (10 mol %), MeCN (0.2 M), and 80 °C. Standard conditions II: 3 (1.0
equiv), 2o (2.0 equiv), In(OTf)3 (20 mol %), HFIP (0.5 M), and 80 °C. bAll reactions were performed on a 0.2 mmol scale unless otherwise
noted. Isolated yields were reported. The minor regioisomeric position is labeled. cGram scale. d1.2 equiv of 2o. eThe deiodinative nitration
product 1-methoxy-2,4-dinitrobenzene (4ee′) was also isolated in a 24% yield. fThe deformylative nitration product 4ee′ was also isolated in a 15%
yield. gIn(OTf)3 (10 mol %), 2o (1.5 equiv), MeCN (0.2 M), and 100 °C.

2i with a C5 alkyl substitution showed much higher reactivity
than 2i. However, 2r and 2s, derived from 2k and 2h,
respectively, showed much lower reactivity. Thus, 2o was
identified as the optimal nitrating reagent in the model
reaction, affording 4a in an 89% yield. The structure of 2o has
been unambiguously confirmed by X-ray crystallographic
analysis (CCDC 2108423). To probe the safety of reagent
2o, its mechanical sensitivity were investigated by both
computational and experimental methods.17 The calculated
h50 value is 56.2 cm, which corresponds to an impact energy
of 13.8 J from a 2.5 kg drop weight. The experimentally
determined impact sensitivity and friction sensitivity are 13.2 J
and 40−42 N, respectively. Therefore, 2o has a medium
sensitivity. Further characterizations by thermal gravimetric
analysis and differential scanning calorimetry (TGA−DSC)
revealed 2o to be stable until 148 °C, whereby an exothermic
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event accompanied by a 9.9% mass loss was observed (for
details, see Figure S1).18 It is worth mentioning that the
molecular weight of 2o is small (Mw = 172.1), which means the
nitration protocol based on 2o will have better atom economy
than most of the previous strategies. Further optimization of
reaction conditions was conducted to make 2o as a versatile
nitrating reagent not only for the activated electron-rich
aromatics but also for the challenging deactivated electron-
deficient substrates (for details, see Tables S5−S14). For
electron-rich aromatics, inexpensive commercial reagent Yb-
(OTf)3 was identified as the optimal catalyst, and the
optimized conditions were as follows: Yb(OTf)3 (10 mol %)
and 2o (1.5 equiv) in MeCN (0.2 M) at 80 °C (standard
conditions I, Table S8). In addition, other Lewis acid (e.g.,
BF3·Et2O) and strong protic acid (e.g., CF3SO3H) were also
suitable catalysts for the nitration of electron-rich aromatics,
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Table 3. Dinitration of Arenes with 2oa,b

a
Standard conditions III: 3 (1.0 equiv), 2o (3.0 equiv), In(OTf)3 (20 mol %), HFIP (0.5 M), and 80 °C. bAll reactions were performed on a 0.2
mmol scale. Isolated yields were reported. c4.0 equiv of 2o was used. d5.0 mmol scale. eThe mononitrated product 1-bromo-3-methoxy-2-methyl-4-
nitrobenzene (5q′) was also formed in a 36% yield. f2.0 equiv of 2o was used.

albeit with inferior efficiency comparing to Yb(OTf)3 (for
details, see Table S7). For deactivated aromatics, inexpensive
reagents In(OTf)3 and 1,1,1,3,3,3-hexafluoroisopropanol
(HFIP)19 were identified as the optimal catalyst and solvent,
respectively, and the optimized conditions were as follows:
In(OTf)3 (20 mol %) and 2o (2.0 equiv) in HFIP (0.5 M) at
80 °C (standard conditions II, Table S14).
With the optimal reaction conditions in hand, we then
started to explore the substrate scope of this nitration method.
As revealed in Table 2A, electron-rich aromatics, e.g., aryl
ethers (3b, 3c), substituted anilides (3p−x), and phenols (3y−
dd), could be smoothly nitrated by 2o under standard
conditions I to afford the desired mononitrated products (4b,
4c, 4q−dd) in 47−99% yields. Benzene and other electron-
rich aromatics should be nitrated under standard conditions
II to get satisfied yields (58−97%). Interestingly, nitration of
substituted phenols with an electron-withdrawing group, e.g.,
trifluoromethyl (4aa), ester (4bb), or nitro (4cc−dd), also
proceeded well, affording the desired products in 50−71%
yields. Arenes with electron-withdrawing substitutions (3rr−
ss) were also suitable substrates under standard conditions II
affording the corresponding nitrated products in 31−99%
yields (Table 2B). Moreover, 2o was also a viable reagent for
the nitration of various heteroaromatics and even alkenes
(Table 2C). For example, benzo[d][1,3]dioxole (3tt), 2,3-
dihydrobenzo[b][1,4]dioxine (3uu), substituted thiophenes
(3vv−ww), benzothiophene (3xx), benzofuran (3yy), DNA
base (uracil) analogue (3zz), and even 1,1-diphenylethylene
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(3zz′) reacted with 2o smoothly to afford the corresponding
nitrated products in 46−84% yields. Notably, owing to the
mild reaction conditions, the nitration proceeded with good
chemoselectivity, and a broad array of functional groups were
tolerated, including alkoxy (4b, 4c, 4e and 4ee),
((trifluoromethyl)sulfonyl)oxy (4d), sulfide (4f), halides
(4h−k, 4p−s, 4y, 4z and 4ee), alkyl (4l−o), protected
amino (4p−x), free phenol (4y−dd), ester (4n, 4bb and 4ss),
trifluoromethyl (4aa), nitro (4cc−dd), and carbonyl (4qq−
ss). Importantly, the regioselectivity of nitration was
predictable. For monosubstituted electron-rich arenes, a
mixture of p- and o-nitrated products were usually formed in
an equal amount or with the former in a slight excess.
However, for 3d, 3e and 3h, the para-nitrated product was
isolated as the dominant or sole one (4d, 4e and 4h), which
was probably owing to the steric and induction effects of the
substitution. For most deactivated arenes with an extra p- or o-
substitution, nitration took place predominantly or solely at the
less sterically hindered meta-position (4gg−oo and 4qq−rr).
However, in the cases of nitration of 1,2-dimethoxy-4-
nitrobenzene (3pp) and 3,4-dimethoxybenzaldehyde (3ss),
the o-nitrated products (4pp and 4ss) were isolated as the sole
products, respectively, which was in stark contrast to 3oo and
3rr. Interestingly, for methyl benzoate (3ff), a substantial o-
nitrated product was also formed besides the major m-nitrated
product. Other salient features of this nitration method were
scalability and recyclability in terms of the pyrazole moiety of
2o. For example, scale-up nitration of substrates 3a (7.0
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Table 4. Late-Stage Nitration of Biorelevant Molecules and Drug Analoguesa
a
All reactions were performed on a 0.2 mmol scale. Isolated yields were reported.
mmol), benzene 3g (15.0 mmol), and 3ii (6.0 mmol) was
successfully achieved to produce the corresponding nitration
products 4a (1.18 g, 97%), 4g (1.70 g, 92%) and 4ii (1.03 g,
86%), respectively. It is worth mentioning that the denitro
product of 2o (i.e., the pyrazole 1o) could be recovered in 78−
94% yields. The scalability and recyclability of this nitration
protocol make it attractive to chemists both in laboratory and
in industry.
Polynitrated arenes are well-known for their application in
high energy materials and other function materials. Never-
theless, their preparation is a formidable challenge since the
introduction of the first nitro group into the aromatic motif
will dramatically decelerate further nitrations.20 Currently,
these special chemicals are predominantly prepared through
multiple separate nitration steps involving the use of extremely
aggressive “mixed acids”.20,21 Therefore, general mild methods
are in urgent need for the synthesis of polynitrated arenes.21c
While probing the scope of nitration by 2o, we noticed that the
nitration of anisole (3b) under standard conditions II
provided the intriguing o,p-dinitrated product 5a in a 40%
yield. Encouraged by this exciting finding, we aimed at
developing an efficient dinitration protocol based on 2o. To
our delight, the yield of dinitration was satisfyingly improved to
82% when 3.0 equiv of 2o was applied, which was set as the
standard protocol for dinitration (standard conditions III).
Gratifyingly, as revealed in Table 3, various electron-rich
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aromatics were suitable substrates for dinitration under
standard conditions III, including monosubstituted anisoles
(5b−i), veratrole derivatives (5j−p), polysubstituted aryl
ethers (5q−t) and sulfonamide (5u). The regioselectivity of
this dinitration protocol was excellent and predictable. For
substituted anisoles (5b−i) and polysubstituted aryl ethers
(5q−t), dinitration took place at the para- and (less-hindered)
ortho-positions of the alkoxy group, with the exception of 3-
methyl anisole, which generated three separable regioisomers:
the major o,p-dinitrated products (5g: 40% and 5g′: 19%) and
the minor o,o′-dinitrated product (5g″: 15%). Different from
the substituted anisoles, dinitration of veratrole derivatives
(5j−p) exclusively occured at the vicinal para-positions of the
two alkoxy groups in excellent yields (79−99%). It was worth
noting that this dinitration protocol was also scalable as
demonstrated by a 5.0 mmol scale dinitration of 1,2-
diethoxybenzene, which afforded 1.04 g of product 5k (86%
yield) alongside 84% recovery of 1o. The structure of 5k was
unambiguously assigned by X-ray crystallographic analysis
(CCDC 2105485). Besides our general dinitration protocol,
three interesting indirect dinitration reactions were also
discovered, including decarboxylative ipso-nitration22a (3bb′
to 4dd), deformylative ipso-nitration22b (3ss to 5j), and
deiodinative ipso-nitration22c (3ee to 5a) (Table 3B). Such
indirect dinitration methods not only supplemented our
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Figure 2. Preliminary mechanistic studies. (aEnergies refer to Gibbs free energy (in kcal mol−1) calculated using M06/6-311+G(d,p)-SDD/
SMD(acetonitrile)//B3LYP-D3(BJ)/6-31G(d)-LANL2D. bAll reactions were performed on a 0.2 mmol scale. GC yields with tridecane as an
internal standard).

dinitration toolbox but also showcased the tunability of the
nitration chemistry based on 2o.
The value of our aromatic nitration method in medicinal
chemistry research was well established by its efficient late-
stage C−H nitration of a series of complex biorelevant
molecules (Table 4). Various drug analogues, including
fenclorim (6a), clofibrate (6b), fenofibrate (6c), isoxepac
(6d), procymidone (6e), veratricaldehyde (6f), nitrofen (6g),
nimesulide (6h), and dicamba (6i) underwent nitration
smoothly, affording the mononitrated products 7a−i in
moderate to good yields (51−99%). In all of these cases,
excellent regioselectivity was observed, presumably corre-
sponding to positions of high electron density and less steric
hindrance of the aromatic motifs. For example, the nitration of
6h took place exclusively on the more electron-rich arene motif
as revealed by X-ray crystallographic analysis (7h, CCDC
2106743). Alternatively, without an especially electron-rich π-
system present, competitive nitrations of the remaining
aromatic sites could be observed. Not surprisingly, nitration
of ibuprofen (6j) and benzbromarone (6k) under conditions
II resulted in mononitration at multiple aromatic positions. In
addition, subjection of triclosan (6l), flurbiprofen (6m), and
gemfibrozil (6n) to our protocol (conditions II) similarly
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resulted in promiscuous mononitrated and dinitrated products,
which were readily separated by column chromatography.
Nevertheless, when 6n was subjected to conditions III, only
the o,p-dinitrated product 7n′ was obtained in a 73% yield,
which showed the potential of tunability of our nitration
method. In the context of drug discovery, the introduction of a
nitro group into a biorelevant molecule usually alters its
physicochemical properties,1a,b,23 including bioreduction po-
tential (prodrugs), pKa value, the hydrophobicity, and steric
size. Additionally, the incorporated nitro group can also serve
as a useful functional handle for further investigation.
Therefore, a facile access to these nitrated derivatives through
a mild late-stage nitration bears the potential for uncovering
new biological activities and functions rapidly.24
To gain insights into the structure−activity relationship
(SAR) of this new series of nitration reagents, preliminary
mechanistic studies were conducted (Figure 2). First, we
performed density functional theory (DFT) calculations to
investigate the dissociation free energy of the N−NO2 bonds
of nitrating reagents 2a, 2i, and 2o, and the following three
different dissociation approaches were taken into account: the
homolytic cleavage (ΔGHomo), heterolytic cleavage (ΔGHet),
and Cu(OTf)2-assisted heterolytic cleavage (ΔGHet(Cu))
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(Figure 2A). The computational results indicated that neither
homolytic cleavage nor heterolytic cleavage of the N−NO2
bond was thermodynamically favorable for the nitration
process. In stark contrast, the calculated ΔGHet(Cu) values of
2a, 2i, and 2o were in the range of 27.7−44.1 kcal/mol, which
were much lower compared to the corresponding ΔGHet. Such
dramatic Gibbs free energy decrease (>24 kcal/mol) indicated
the heterolytic cleavage of the N−NO2 bond was significantly
facilitated by Cu(OTf)2. Impressively, the calculated ΔGHet(Cu)
could also well explain the observed “substituent effects” on
nitrating activity shown in Table 1B. For instance, the
introduction of a nitro group into 2a led to an over 15 kcal/
mol decrease of ΔGHet(Cu) for 2i and 2o, which was tentatively
named the “nitro effect”. An additional methyl substitution to
2i led to a further 0.5 kcal/mol decrease of ΔGHet(Cu) for 2o,
which was tentatively named the “methyl effect”. The “nitro
effect” could be rationalized on the ground that the 3-NO2
group of 2i and 2o would stabilize the generated anion and
promote the coordination with Cu(OTf)2 after the heterolytic
cleavage of the N−NO2 bond. A plausible explanation for the
“methyl effect” was the introduction of a 5-methyl substituent
into the pyrazole nucleus that might impede the nitro group
from achieving coplanarity with the pyrazole ring and reduce
the ratio of the double-bond character of the N−NO2 bond in
resonance structures, thus weakening this N−NO2 bond in 2o.
Indeed, the X-ray crystallographic analysis of 2o (CCDC
2108423) shows that the N−NO2 bond length (1.435 Å)
(Table S18) was considerably longer than in 2a (1.399 Å)25
(Figure 2A). In addition, 2p, the methylene congener of 2o,
exhibited equally excellent nitrating reactivity as 2o (Table
1B). Therefore, the X-ray structural information and the case
of 2p strongly supported our explanation for both the “methyl
effect” and the “nitro effect”. Moreover, the reaction profile
studies also clearly demonstrated the superiority of reagent 2o
over 2a and 2i in terms of nitration reactivity and efficiency
(Figure 2B). Thus, the “nitro effect” and the “methyl effect” on
tuning the nitration reactivity of the reagents 2a, 2i, and 2o are
other striking examples of the SAR study that will surely inspire
the development of next generation of nitration reagents.
Next, a competitive kinetic isotope effect (KIE) experiment
between naphthalene (3a) and d8-naphthalene was performed
(Table S17), and the measured KIE was 0.88, indicating a
secondary isotope effect, which is consistent with the previous
studies by Olah26 and Katayev.12f Moreover, we performed a
series of radical trapping control experiments, exemplified by
performing the nitration of naphthalene (3a) with 2o in the
presence of a radical scavenger (Table S16). As a result, no
significant inhibition of nitration was observed. Therefore,
both DFT calculations and the above control experiments
favor an electrophilic aromatic nitration over a radical
process.3a,27 Moreover, probing the intriguing dinitration
process, we carefully analyzed the selected data from Tables
2 and 3. As shown in Figure 2C, the reaction of anisole 3b with
2o under conditions I achieved the first nitration to afford
mononitrated 4b as a mixture of 3nn and 3oo. Next, 3nn, 3oo,
and 3pp further reacted with 2o under conditions II to
achieve the second nitration, providing the dinitrated products
5a (4nn/4oo) and 5j (4pp) in excellent yields. These results
supported the finding that the mild dinitration process actually
went through a stepwise nitration mechanism. Currently, we
are working on elucidating the mechanisms of the indirect
dinitration reactions of Table 3B.
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In conclusion, we have developed a practical N−H nitration
method for the establishment of a diversified N-nitro-type
reagent library from which a powerful nitration reagent 5-
methyl-1,3-dinitro-1H-pyrazole (2o) was identified. 2o be-
haves as a controllable source of the nitronium ion with good
atom economy, enabling mild and scalable nitration and
dinitration protocols for a broad range of (hetero)arenes
bearing various functional groups. Of note, the nitration is
controllable through manipulating reaction conditions to
furnish mononitrated or dinitrated product selectively. The
value of this aromatic nitration method in medicinal chemistry
research has been well established by its efficient late-stage C−
H nitration of a series of complex biorelevant molecules. DFT
calculations and preliminary mechanistic study reveal that the
powerfulness and versatility of 2o are due to the synergistic
“nitro effect” and “methyl effect”. Heterolytic cleavage of the
N−NO2 bond in 2o is greatly facilitated by a Lewis acid
catalyst, thereby suggesting an electrophilic aromatic nitration
mechanism.
■ METHODS
General Procedure for the Synthesis of Nitrating Reagents
A 250 mL sealed tube equipped with a magnetic stir bar was charged
under O2 with 1 (3.0 mmol, 1.0 equiv), TBN (0.31 g, 3.0 mmol, 1.0
equiv), CAN (3.2 g, 6.0 mmol, 2.0 equiv) and MeCN (20.0 mL). The
reaction mixture was then heated to 100 °C and stirred. After
completion of the reaction (about 16 h, monitored by TLC), the
mixture was cooled to room temperature (rt), filtered through a thin
pad of celite eluting with ethyl acetate (EtOAc), and the combined
filtrate was concentrated in vacuo. The residue was directly purified by
column chromatography on silica gel (petroleum ether (PE)/EtOAc
= 5:1) to give the desired product 2.
Standard Conditions I for the Nitration of Aromatics
A 10 mL oven-dried vial equipped with a magnetic stir bar was
charged with 3 (0.2 mmol, 1.0 equiv), 2o (51.2 mg, 0.3 mmol, 1.5
equiv), Yb(OTf)3 (12.4 mg, 0.02 mmol, 10 mol %) and dry MeCN
(1.0 mL). The reaction mixture was then heated to 80 °C and stirred.
After completion of the reaction (about 16 h, monitored by TLC),
the mixture was cooled to rt, filtered through a thin pad of celite
eluting with ethyl acetate (10 mL), and the combined filtrate was
concentrated in vacuo. The residue was directly purified by column
chromatography on silica gel (PE/EtOAc = 10:1) to give the desired
product 4.
■
*
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacsau.2c00413.
Experimental procedures, characterization data of
products, calculation details, and X-ray crystallographic
data for 2o, 5k, and 7h (PDF)
■ AUTHOR INFORMATION
Corresponding Authors
Liangwei Shi − CAS Key Laboratory of Energy Regulation
Materials, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, China;
Email: fjptslwcj@sioc.ac.cn
Qianghui Zhou − The Institute for Advanced Studies, Wuhan
University, Wuhan 430072, China; Sauvage Center for
Molecular Sciences, Engineering Research Center of
Organosilicon Compounds & Materials (Ministry of
https://doi.org/10.1021/jacsau.2c00413
JACS Au 2022, 2, 2152−2161
JACS Au pubs.acs.org/jacsau
Education), Hubei Key Lab on Organic and Polymeric
OptoElectronic Materials, College of Chemistry and
Molecular Sciences, Wuhan University, Wuhan 430072,
China; TaiKang Center for Life and Medical Sciences,
Wuhan University, 430072 Wuhan, China; State Key
Laboratory of Bio-Organic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China; orcid.org/0000-0002-
8125-0380; Email: qhzhou@whu.edu.cn
Lin Zhuang − The Institute for Advanced Studies, Wuhan
University, Wuhan 430072, China; Sauvage Center for
Molecular Sciences, Engineering Research Center of
Organosilicon Compounds & Materials (Ministry of
Education), Hubei Key Lab on Organic and Polymeric
OptoElectronic Materials, College of Chemistry and
Molecular Sciences, Wuhan University, Wuhan 430072,
China; orcid.org/0000-0002-5642-6735;
Email: lzhuang@whu.edu.cn
Authors
Tao Yang − The Institute for Advanced Studies, Wuhan
University, Wuhan 430072, China
Xiaoqian Li − Sauvage Center for Molecular Sciences,
Engineering Research Center of Organosilicon Compounds &
Materials (Ministry of Education), Hubei Key Lab on
Organic and Polymeric OptoElectronic Materials, College of
Chemistry and Molecular Sciences, Wuhan University,
Wuhan 430072, China
Shuang Deng − Sauvage Center for Molecular Sciences,
Engineering Research Center of Organosilicon Compounds &
Materials (Ministry of Education), Hubei Key Lab on
Organic and Polymeric OptoElectronic Materials, College of
Chemistry and Molecular Sciences, Wuhan University,
Wuhan 430072, China
Xiaotian Qi − Sauvage Center for Molecular Sciences,
Engineering Research Center of Organosilicon Compounds &
Materials (Ministry of Education), Hubei Key Lab on
Organic and Polymeric OptoElectronic Materials, College of
Chemistry and Molecular Sciences, Wuhan University,
Wuhan 430072, China; orcid.org/0000-0001-5420-
5958
Hengjiang Cong − Sauvage Center for Molecular Sciences,
Engineering Research Center of Organosilicon Compounds &
Materials (Ministry of Education), Hubei Key Lab on
Organic and Polymeric OptoElectronic Materials, College of
Chemistry and Molecular Sciences, Wuhan University,
Wuhan 430072, China; orcid.org/0000-0002-9225-
0095
Hong-Gang Cheng − Sauvage Center for Molecular Sciences,
Engineering Research Center of Organosilicon Compounds &
Materials (Ministry of Education), Hubei Key Lab on
Organic and Polymeric OptoElectronic Materials, College of
Chemistry and Molecular Sciences, Wuhan University,
Wuhan 430072, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacsau.2c00413
Notes
The authors declare no competing financial interest.
2160
Article
■ ACKNOWLEDGMENTS
The authors are grateful to the National Key Research and
Development Program of China (No. 2016YFB0101203) and
the Wuhan University for financial support. They gratefully
acknowledge Profs. M. Teng (Baylor College of Medicine),
W.-B. Liu, and Y.-H. Chen (Wuhan University) for helpful
discussions; Prof. D. Gu (Wuhan University) for TG-DSC
analysis; and Dr. Y. Liu (Kura Oncology, Inc.) and Dr. H.-Q.
Dong (Arvinas, Inc.) for help with the preparation of the
manuscript. We thank the Core Facility of Wuhan University
for instrumental TGA analysis. The numerical calculations in
this paper were done on the supercomputing system in the
Supercomputing Center of Wuhan University.
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