Transition-metal-free mono- or dinitration of protected anilines

Article abstract of DOI:10.1080/00397911.2020.1752730

An amide-assisted arene nitration is presented, and both mono- and dinitration of protected anilines could be effected by using NaNO₂ and NaNO₃ as the mono- and bisnitrating agents, respectively. This divergent synthesis is transition-metal- and acid-free, and features a broad substrate scope, low cost, and ortho–para selectivity.

Full text of DOI:10.1080/00397911.2020.1752730

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Transition-metal-free mono- or dinitration of
protected anilines
Enrui Dai, Yongrui Dong, Rui Kong, Guangzhang Liu, Ying Dong, Qiong Wu,
Deqiang Liang & Yinhai Ma
To cite this article: Enrui Dai, Yongrui Dong, Rui Kong, Guangzhang Liu, Ying Dong, Qiong Wu,
Deqiang Liang & Yinhai Ma (2020): Transition-metal-free mono- or dinitration of protected anilines,
Synthetic Communications, DOI: 10.1080/00397911.2020.1752730
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https://doi.org/10.1080/00397911.2020.1752730
Transition-metal-free mono- or dinitration of
protected anilines
Enrui Daia, Yongrui Donga, Rui Konga, Guangzhang Liua, Ying Dongb, Qiong Wuc,
Deqiang Lianga,c , and Yinhai Maa
b
aSchool of Chemistry and Chemical Engineering, Kunming University, Kunming, China; College of
Chemistry, Chemical Engineering and Materials Science, Shandong Normal University, Jinan, China;
cYunnan Engineering Technology Research Center for Plastic Films, Kunming, China
ABSTRACT
ARTICLE HISTORY
Received 24 January 2020
An amide-assisted arene nitration is presented, and both mono- and
dinitration of protected anilines could be effected by using NaNO2
and NaNO3 as the mono- and bisnitrating agents, respectively. This
divergent synthesis is transition-metal- and acid-free, and features a
broad substrate scope, low cost, and ortho–para selectivity.
KEYWORDS
Amide-assisted strategy;
anilides; C ꢀ H
functionalization; divergent
synthesis; radical reaction
GRAPHICAL ABSTRACT
Introduction
C ꢀ H bond functionalization is a highly appealing synthetic methodology due to its
atom- and step-economy.[1] Arene C ꢀ H functionalization could be achieved through
the cross coupling of p-excessive systems with either electrophiles[2] or electrophilic rad-
icals,[3] and chelation-assisted[4] or non-directed C ꢀ H bond activation protocols[5]
have significantly expanded the tool box of synthetic chemists (Scheme 1). In 2017, we
developed a complementary amide-assisted strategy for arene C ꢀ H functionalization,
by which the challenging radical aromatic C–H fluorination was effected.[6] The amide
group could be readily removed and this amide-assisted strategy is powerful as evi-
denced by several recent elegant reports.[7]
Nitroarenes are finding increasing applications in the fields of dyes, pharmaceuticals,
plastics, and explosives, and the installation of the nitro group is a fundamental trans-
formation in organic chemistry.[8] In the regard of the nitration reaction of protected
anilines, great efforts have been made. The mixed acid system of HNO3/H2SO4 is trad-
itionally used as both the nitrating agent and the solvent,[9] and some recent methods
still require an excess of acids.[10] Fe(NO3)3,[11] Cu(NO3)2,[12,13] AgNO3,[13]
CONTACT Deqiang Liang
liangdq695@nenu.edu.cn
School of Chemistry and Chemical Engineering, Kunming
University, Kunming 650214, China; Yunnan Engineering Technology Research Center for Plastic Films, Kunming
650214, China.
Supplemental data for this article is available online at https://doi.org/10.1080/00397911.2020.1752730
ß 2020 Taylor & Francis Group, LLC

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E. DAI ET AL.
Scheme 1. Strategies for arene C ꢀ H functionalization.
Bi(NO3)3,[14] tert-butyl nitrite (TBN),[15] and azidotrimethylsilane (TMSN3)[16] are also
good nitro sources, yet the reactions using them are associated with large amounts of
transition metals, directing groups and/or limited substrate scopes. Similarly, the sub-
strates of the mononitration reaction using sodium nitrite developed by Kianmehr and
coworkers are limited to anilides, and the AgNO2 catalyst is essential.[17] Very recently,
Shao and coworkers disclosed a transition-metal-free synthesis of nitroarylamines under
mild conditions, which is associated with a narrow scope of the N-protecting group
(PG).[18] Konig and coworkers reported a photocatalytic nitration of protected anilines
€
using an expensive photosensitizer, and N-sulfonyl substrates are not compatible with
this transformation either.[19] Furthermore, despite the plethora of arene mononitration
reactions, methodologies for arene dinitration are extremely rare,[11c,15a] probably owing
to the strongly electron-withdrawing nature of the nitro group. Thus, the development
of an acid- and transition-metal-free mono- or dinitration reaction of protected anilines
with a broad substrate scope is still highly desirable. In continuation of our interest in
radical chemistry,[20] herein we report such a reaction, using NaNO2 and NaNO3 as the
mono- and bisnitrating agents, respectively, and featuring ortho–para selectivity.
Results and discussion
We began our studies by investigating the nitration of N-(4-(tert-butyl)phenyl)acetamide
1a with NaNO2 as the NO2 source (Table 1). Exposure of anilide 1a to 1.2 equiv. of
NaNO2 and 3 equiv. of K2S2O8 at 120 ꢁC for 12 h in acetonitrile furnished desired
ortho-mono-nitrated product 2a in 76% yield (entry 1). K2S2O8 as the initiator is essen-
tial. Using (NH4)2S2O8 or Oxone instead of K2S2O8, 2-nitroanilide 2a was formed in
diminished yields (entries 2 and 3), whereas tert-butyl hydroperoxide (TBHP, entry 4),
di-tert-butyl peroxide (DTBP, entry 5), tert-butyl peroxybenzoate (TBPB, entry 6), ben-
zoyl peroxide (BPO, entry 7), and phenyliodine diacetate (PIDA, entry 8) all proved
ineffective for this transformation. Then, a survey of a series of reaction media was con-
ducted. While 2a was produced in 45% yield using nitromethane as the solvent (entry
11), the use of other tested solvents, including toluene (entry 9), 1,2-dichloroethane
(DCE, entry 10), tetrahydrofuran (THF, entry 12), N,N-dimethylformamide (DMF, entry
13), dimethylsulfoxide (DMSO, entry 14) and methanol (entry 15), all led to extremely
low nitration efficiency. Interestingly, when the reaction was run using 3 equiv. of
NaNO3 instead of NaNO2 and at an elevated temperature of 140 ꢁC, dinitration

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Table 1. Screening of reaction conditions.a
Entry
Oxidant
Solvent
Yield of 2a (%)
Yield of 3a (%)
1
2
3
4
5
6
7
8
K2S2O8
(NH4)2S2O8
Oxone
TBHPb
DTBP
TBPB
BPO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Toluene
DCE
MeNO2
THF
DMF
DMSO
MeOH
MeCN
76
55
12
nr
nr
nr
Trace
0
nr
8
45
nr
nr
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
61
PIDA
9
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
10
11
12
13
14
15
16c
0
TRACE
TRACE
aReaction conditions: 1a (0.2 mmol), NaNO2 (0.24 mmol), oxidant (0.6 mmol), solvent (2 mL), 120 ꢁC, Ar, 12 h.
b70% solution in water.
cNaNO3 (3 equiv.) was used instead of NaNO2, and the reaction mixture was stirred at 140 ꢁC for 24 h.
occurred and dinitrated anilide 3a was furnished in 61% yield after 24 h. Thus, here we
present a divergent synthesis of both mono- and dinitroarenes from protected anilines,
using NaNO2 and NaNO3 as the mono- and bisnitrating agents, respectively.
Under the optimized conditions for the mononitration reaction, the scope of the pro-
tected anilines was explored (Table 2). First, we examined a variety of electron-withdrawing
N-PGs. Anilines protected by an aliphatic acyl group, such as propionyl (2b1), octanoyl
(2b2), decanoyl (2b3), dodecanoyl (2b4), stearoyl (2b5), or pivaloyl group (2b6), all proved
to be competent substrates, with the expected mononitrated products 2b1–6 obtained in
62–75% yields. Aroyl-protected 4-(tert-butyl)anilines, bearing electron-neutral (2c1), -donat-
ing (2c2) or -withdrawing substituents (2c3–7) on the aroyl ring at para-, meta-, or ortho-
positions, are suitable substrates as well, and the electronic nature of these substituents plays
a poor role in the reaction, furnishing the corresponding 2-nitroanilides 2c1–7 in high
yields. Sulfonyl PGs were also tolerated, and methylsulfonyl- (2d1), ethylsulfonyl- (2d2),
phenylsulfonyl- (2e1), or o-tolylsulfonyl-protected anilines (2e2) all reacted smoothly to
afford the corresponding 2-nitrosulfonamide products 2d,e in moderate to high yields.
Various N-aryl groups were then evaluated. Whereas the reactions of acetanilides hav-
ing either an electron-rich (2f1,2) or -deficient para-substituted N-aryl group (2f3,4) fur-
nished the desired 2-nitroacetanilides 2f1–4 albeit in moderate yields. When this method
was applied to meta- (2g1,2) or ortho-mono-substituted acetanilides (2h), poor ortho to
para selectivity was noticed, representing a limitation of the current protocol. While two
ortho-nitrated regioisomers were also delivered in the reaction of 4-bromo-3-methyl acet-
anilide (2j), the use of 2,4-dimethyl acetanilide, in which the para-position and one of
the ortho-positions are blocked, gave the ortho-nitro product 2i as the only product.

4
E. DAI ET AL.
Table 2. Mononitration of protected anilines.a
aReaction conditions: 1 (0.2 mmol), NaNO2 (0.24 mmol), K2S2O8 (0.6 mmol), CH3CN (2 mL), Ar, 120 ꢁC, 12 h.
bSeparable regioisomers were obtained.
With anilides bearing no substituent on the N-aryl ring, the nitrations occurred preferen-
tially at the ortho-position over the para-position to a small extent, and the steric effect
does not seem to play a significant role (2k1–3).
The scope of the dinitration reaction was also investigated (Table 3). Using 3 equiv. of
NaNO3 as the NO2 source and at 140 ꢁC, N-(4-(tert-butyl)phenyl)propionamide partici-
pated in this reaction smoothly to afford dinitrated anilide 3b in 57% yield after 24 h,
whereas the steric effect of the octanoyl group might play a noticeable role in the reaction
kinetics, resulting in incomplete dinitration even after a prolonged reaction time of 48 h
(3c). The dinitration was further extended to benzoyl- (3d), methylsulfonyl- (3e), ethyl-
sulfonyl- (3f), and phenylsulfonyl-protected 4-(tert-butyl)anilines (3 g), and the related

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Table 3. Dinitration of protected anilines.a
aReaction conditions: 1 (0.2 mmol), NaNO3 (0.6 mmol), K2S2O8 (0.6 mmol), CH3CN (2 mL), Ar, 140 ꢁC, 24 h.
bThe reaction time was prolonged to 48 h.
2,6-dinitro products 3d–g were afforded in 57–67% yields. In the case of N-(p-tolyl)aceta-
mide, degradation might occur as a side reaction due to the intolerance of the arylme-
thane moiety under radical conditions (3h).[17] An acetanilide with an electron-deficient
N-aryl group is less active, and the corresponding dinitroanilide 3i was formed in only
38% yield even after 48 h. When the para-positions were not blocked, 2,4-dinitration
occurred, furnishing 2,4-dinitroanilines 3j–l in moderate yields.
Neither mono- nor dinitration occurred with N-(4-(tert-butyl)phenyl)-N-methylacetamide
or N-(4-(tert-butyl)phenyl)-N-(methylsulfonyl)methanesulfonamide as the substrate (Scheme
2), indicating that the N–H amide group is crucial. To further probe the reaction mechanism,
radical trapping experiments were performed. Upon addition of 2,2,6,6-tetramethylpiperi-
dine-1-oxyl (TEMPO, 1.2 equiv.), butylated hydroxytoluene (BHT, 1.2 equiv.) or 1,1-diphe-
nylethylene (DPE, 2 equiv.) as the radical scavenger, the model reactions under otherwise
standard conditions for the mononitration were completely suppressed. Furthermore, the
acetanilide reacted with BHT under mononitration conditions to afford acetanilide-BHT
adduct 4 in 4% yield, indicating that the amidyl radical might be involved in the title reaction.
On the basis of the above observations and previous works,[6,7,10b,13d,16,18,19] a rad-
ical-radical cross-coupling mechanism is proposed (Scheme 3). In the beginning, the
single-electron transfer (SET) from K2S2O8 to substrate 1a occurs to yield the N-radical
cation A, the deprotonation of which gives the anilidyl N-radical intermediate B. Owing

6
E. DAI ET AL.
Scheme 2. Control experiments.
Scheme 3. Mechanistic proposal.
to resonance delocalization, ortho-carbon-centered radical C is also a resonance con-
tributor, and it reacts with nitrogen dioxide radical, a persistent radical generated from
NaNO2 through SET from K2S2O8, to afford the dearomatized intermediate D. D read-
ily undergoes tautomerization to release the nitroanilide product 2a.
Conclusions
In conclusion, a transition-metal- and acid-free nitration of protected anilines is pre-
sented, and both mono- and dinitration could be affected by using NaNO2 and NaNO3
as the mono- and bisnitrating agents, respectively. The N-H moiety is crucial, and this
divergent synthesis features a broad substrate scope, low cost, and ortho–para selectivity.
Experimental
Chemicals were purchased from commercial sources and used without treatment unless
stated otherwise. Reactions were monitored by thin layer chromatography (TLC) using
silica gel F254 plates. Products were purified by column chromatography over 300–400
1
mesh silica gel under a positive pressure of air. H NMR and 13C NMR spectra were
recorded at 25 ꢁC on a Bruker AscendTM 400 spectrometer using tetramethyl silane

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SYNTHETIC COMMUNICATIONSV
7
(TMS) as an internal standard. High-resolution mass spectra (HRMS) were obtained
using a Bruker microTOF II Focus spectrometer (ESI).
General procedure (taking the synthesis of 2a as an example)
A 10-mL screw-capped Schlenk tube, equipped with a magnetic stirring bar, was charged
under argon with N-(4-(tert-butyl)phenyl)acetamide 1a (38 mg, 0.2 mmol), NaNO2 (17 mg,
0.24 mmol), and K2S2O8 (162 mg, 0.6 mmol), followed by the addition of MeCN (2.0 mL).
The tube is sealed and the mixture was stirred at 120 ꢁC for 12 h; then it was quenched
with saturated aqueous Na2S2O3 (1.0 mL) and water (10.0 mL), and extracted with CH2Cl2
(10.0 mL) three times. The residue obtained after evaporation of the solvent was purified by
column chromatography on silica gel (petroleum ether/ethyl acetate ¼ 24:1, v/v) to afford
1
N-(4-(tert-butyl)-2-nitrophenyl)acetamide 2a as a pale yellow solid (36 mg, 76% yield). H
NMR (400 MHz, CDCl3) d ¼ 10.20 (brs, 1H), 8.64 (d, J¼ 8.9 Hz, 1H), 8.18 (d, J¼ 2.3 Hz,
1
1H), 7.68 (dd, J¼ 8.9, 2.3 Hz, 1H), 2.28 (s, 3H), 1.34 (s, 9H); 13Cf Hg NMR (100 MHz,
CDCl3) d ¼ 167.9, 145.9, 135.2, 132.4, 131.3, 121.1, 121.0, 33.6, 29.9, 24.5; HRMS (ESI-TOF)
þ
Calcd for C12H17N2O3 ([M þ H]þ) 237.1234. Found 237.1233.
1
Full experimental details, spectral data of the products, and H and 13C NMR spectra
can be found via the “Supplementary content” section of this article’s Web page.
Funding
We gratefully acknowledge the financial support from the Basic Research Programs of Yunnan
Province [2018FD028, 2018FH001-002], the Scientific Research Funds of Yunnan Education
Department [2017ZDX048], the Research Foundation for Introduced Talents of Kunming
University [YJL19001], the National Natural Science Foundation of China [21702083], the
Yunnan Ten Thousand Talent Program for Young Top-Notch Talents, and the Program for
Innovative Research Team (in Science and Technology) in Universities of Yunnan Province.
ORCID
Deqiang Liang
http://orcid.org/0000-0003-0482-0527
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