Amide-Oxazoline Directed ortho-C–H Nitration Mediated by CuII

Article abstract of DOI:10.1002/ejoc.201900117

A Cu^II-mediated ortho-C–H nitration using amide-oxazoline as the directing group has been developed. The reactions utilize sodium nitrite as the source of the nitro group under O₂ atmosphere and proceed smoothly. The desired products can be obtained in yields of 26–94 %.

Full text of DOI:10.1002/ejoc.201900117

A Journal of
Accepted Article
Title: Amide-Oxazoline directed Ortho-C-H Nitration under Cu(II)-
Mediated
Authors: Tian-Hong Gao, Chun-Meng Wang, Kai-Xiang Tang, Yun-Gen
Xu, and Li-Ping Sun
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900117
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900117
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10.1002/ejoc.201900117
European Journal of Organic Chemistry
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Amide-Oxazoline directed Ortho-C-H Nitration under Cu(II)-
Mediated
Tian-Hong Gao,[a] Chun-Meng Wang,[a] Kai-Xiang Tang,[a] Yun-Gen Xu,[a] and Li-Ping Sun *[a]
Abstract:
A Cu(II)-mediated ortho-C-H nitration using amide-
extent, limitations still remain such as poor regioselectivity
and terrible functional group tolerance due to the harsh
reaction conditions.[12] To solve these problems, transition-
metal-catalyzed or -mediated, chelation-assisted direct
oxazoline as the directing group has been developed. The reactions
utilize sodium nitrite as the source of the nitro group under O2
atmosphere and proceed smoothly. The desired products can be got
in yields of 26-94%.
regioselective aromatic C-H nitrations under
a
mild
condition have got much attention.[13] In addition, Guo and
co-workers have accomplished the Ni-catalyzed remote C-
H nitration of 2-aryl oxazolines, which undergoes a single
electron transfer (SET) pathway.[14] Inspired by above
content, we envisioned that if amide-oxazoline could be
used as a bidentate auxiliary for the ortho nitration of
arenes. Herein we report the first example of a Cu(II)-
mediated, amide-oxazoline group-assisted ortho nitration of
benzoic acid derivatives.
Introduction
Transition-metal-catalyzed C-H functionalization is
becoming an attractive alternative, in recent years, for the
formation of carbon-carbon and carbon-heteroatom bonds.
[1]
During the development of C-H functionalization,
chelation-directed strategy that provides a powerful tool to
enhance the efficiency and control the selectivity of C–H
activation has caught more attention,[2] especially bidentate
auxiliaries[3]. They can form an extremely stable bidentate
metallocycle complex to improve the reactivity.[4] In this
regard, 8-aminoquinoline, used as a bidentate auxiliary
directing group, has been widely reported for the
functionalization of C-H bonds[3,5] since the pioneering work
of Daugulis and co-workers.6 It can form a five-membered
bis-dentate complex with a metal center.[6,7] In comparison,
amide-oxazoline, prevalent organic motifs of relevance to
functional molecules and medicinal chemistry (Figure 1),[8]
can form
complex[9] leading to its reactivity different from amide-
quinoline DG. As consequence, the further
a
six-membered bis-dentate metallocycle
a
functionalization of substituted amide oxazolines has
attracted tremendous interest. At this point, although some
significant progress has been made, such as arylation[10a]
,
Figure 1. Representative application of molecules containing amide-oxazoline
scaffolds.
trifluoromethylation[10b], hydroxylation[10c], amination[10d] etc.,
ortho C-H nitration has not been reported and still
represents a great challenge.
Results and Discussion
The incorporation of the nitro group into aromatics is of
great significance to the chemical industry. Aromatic nitro
compounds are very useful intermediates to construct
various dyes, explosives, pharmaceuticals, plastics as well
as natural products.[11] In term of its preparation, the
We commenced our studies with amide 1a as the model
substrate to optimize reaction parameters (Table 1).
Treating 1a with
2 equivalents of Cu(OAc)2•H2O, 3
equivalents of NaNO2, 2 equivalents of K2HPO4 in DMSO at
80 °C under air gave the desired nitration product 2a in
57% yield (Table 1, entry 1). The use of other solvents such
as DMF, DCE, CH3CN didn't give good results (Table 1,
entries 2-4). Then we considered the dosage of NaNO2.
But whether elevate or decrease amount gave
unsatisfactory results (Table 1, entries 5 and 6). After a
brief screening of bases, K2HPO4 remained the optimal
choice (Table 1, entries 7 and 8). In a set of Cu salt type
and amount screened, 2 equivalents of Cu(OAc)2•H2O was
classical method is to use
a
mixed acid system
(HNO3/H2SO4) and its derivatives as electrophilic nitrating
reagents. Although these methods are useful to some
[a]
T.-H. Gao, Dr. C.-M. Wang, K.-X. Tang, Prof. Dr. Y.-G. Xu, Prof. Dr.
L.-P. Sun
Jiagsu Key Laboratory of Drug Design & Optimization, Department
of Medicinal Chemistry, China Pharmaceutical University,
24 Tongjiaxiang, Nanjing 210009, P.R. China
E-mail: chslp@cpu.edu.cn
Supporting information for this article is available on the WWW
under http://
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10.1002/ejoc.201900117
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Table 1. Optimization of Reaction Conditionsa
Table 2. Scope of Nitration Reactiona,b
Entry
1
Cu salt
base
solvent
DMSO
DMF
yield/%b
57
40
0
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
KOAc
K2CO3
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
/
2
3
DCE
4
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
0
5c
20
50
49
47
55
0
6d
7
8
9
10
11
12e
13f
14f
15g
16f
17g
Cu(OTf)2
CuCl2
25
50
87
87
80
80
92
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2
/
/
Cu(OAc)2
/
aReaction Conditions: 1a (0.1 mmol), Cu salt (0.2 mmol), NaNO2 (0.3 mmol),
base (0.2 mmol), solvent (1 mL), 12 h, 80 °C. bIsolated yield. cNaNO2 (0.4
mmol). dNaNO2 (0.15 mmol). eCu(OAc)2•H2O (0.1 mmol). fThe reaction was
carried out under O2 at 70 °C. gThe reaction was carried out under O2 at
60 °C.
aReaction Conditions: 1 (0.1 mmol), Cu(OAc)2 (0.2 mmol), NaNO2 (0.3 mmol),
DMSO (1 mL) , 1.5~12 h, 50~70 °C. bIsolated yield.
still the best choice (Table 1, entries 9-12). But beyond that,
2). Substrates containing both electron-donating and –
withdrawing substituents at the ortho position afforded the
desired products (2a–2d) in excellent yields except o-chloro
and o-bromo substrates. They could be substituted by NO2
2
equivalents of Cu(OAc)2 demonstrated comparable
efficiency (Table 1, entry 9). Subsequently, temperature
and atmosphere were taken into consideration. To our
delight, when we made the reaction at 70 °C under O2
atmosphere, the yield of 2a raised to 87% (Table 1, entry
13). Furthermore, the base K2HPO4 was not essential
(Table 1, entry 14). Afterward, we kept lowering the
temperature to 60 °C on the basis of entry 14, but we did
not obtain the better yield (Table 1, entry 15). Given the
comparable efficiency of Cu(OAc)2 in our initial screen
stages, we used Cu(OAc)2 instead of Cu(OAc)2•H2O and
react at 70 °C and 60 °C under O2 separately (Table 1,
entries 16 and 17). To our surprise, the yield increased to
92% when 2 equivalents of Cu(OAc)2 was employed at
60 °C under O2. Finally, the optimum choice for the reaction
was identified as follows: 2 equivalents of Cu(OAc)2, 3
equivalents of NaNO2 as nitro source and DMSO as the
solvent under O2 atmosphere at 60 °C.
especially
o-bromo (2e, 2f). Bisubstituted substrates
reacted without affecting the yields significantly (2g–2j
,
82%-93% yields). 2,4-dichloro substituted substrate was
also replaced by NO2 at ortho-position, and then gained
product 2k'. For non- or para-substituted substrates, only
double ortho-nitration products could be obtained (2l–2p).
However, mono and double products could be got together,
when a meta-substituent was borne on the benzene ring
(2q-1 and 2q-2). Unfortunately, the reaction conditions
could not be extended to the heterocyclic system (2r).
In order to explore more about the scalability of this
methodology, we conducted a gram scale reaction with 1a
(Scheme 1). And the target product was gained in 78%
yield.
To probe the reaction mechanism, we carried out
several control experiments (Scheme 2). Firstly, 1l-d5 was
prepared and transformed under the optimized reaction
Having the optimal conditions in hand, we then explored
the scope of benzamide substrates for this reaction (Table
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10.1002/ejoc.201900117
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conditions to conduct the intermolecular competition
experiment (Scheme 2, Eq.(1)). The intermolecular kH/kD of
1l to 1l-d5 was determined to be 2.3, indicating that the
ortho C-H bond cleavage was involved in the rate-
determining step. Then, we added radical scavenger
2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO, 2 equiv.) to
the standard condition (Scheme 2, Eq.(2)). The yield was
of amide-oxazoline DG, a six-membered copper complex 5
is formed. Then copper complex undergoes C-H activation
to form the aryl/Cu(II) intermediate
6
, followed by the
7 [15]
next reacts
, which
undergoes reductive elimination to afford the desired
nitration product 2a
oxidation of copper (II–III) complex
6
–
.
7
with sodium nitrite to generate the copper complex
8
.
negligibly affected which suggested that
a
radical
As for the formation of by-products, we speculate that
during the process of C-H activation, the C-X (X=Cl, Br)
bond is also activated and cleaves to form an
organometallic intermediate, next undergoes nitration. So,
the halogen is substituted by NO2, and then by-products are
obtained.
intermediate might not participate in the reaction. Next,
when we used the equivalent of an electron-rich substrate
(1a) and electron-deficient substrate (1c) to explore the
electronic effect (Scheme 2, Eq.(3)), the products 2a and 2c
were isolated in equal yields, showing that the electronic
nature of substituents had minimal impact on the reactivity
of the substrates. Finally, the effect of directing group was
examined (Scheme 2, Eq.(4)). No product was generated
when a monodentate directing group substrate
structure similar to 1a was attempted in the reaction,
indicating that bidentate coordinating group is
3 with
a
indispensable for this nitrification.
Scheme 3. Proposed Mechanism
Conclusions
Scheme 1. Gram Scale Reaction
In summary, we have developed the first copper(II)-
mediated ortho C-H bond nitration using an amide-
oxazoline directing group. The reaction process proceeds
smoothly, uses easily accessible earth-abundant copper
reagent, simple and readily available nitro source, and is
free of base. This method enriches the construction of nitro
compounds as well as proves more possibilities of amide-
oxazoline directing group.
Experimental Section
General Information: Unless otherwise noted, all chemical reagents
were commercially purchased and used without further purification.
Analytical TLC was carried out by using pre-254 coated plates and
visualized with UV light. Melting points (uncorrected) were determined on
a RY-1 MP apparatus. 1H and 13C NMR spectra were recorded on a
Bruker AV-300 spectrometer at 300 MHz and 75 MHz, respectively.
Chemical shifts are reported in δ (ppm), relative to the internal standard
of TMS. The signals observed are described as: s (singlet), d (doublet), t
(triplet), q (quartet), m (multiple). Coupling constants are reported as J
values in units of Hz. Mass spectrometry was obtained by using a Q-TOF
high-resolution mass spectrometer. Flash column chromatography was
performed over silica gel 200-300 m.
Scheme 2. Control Experiments
General Procedure for the Substrates 1a-1r: All the starting substrates
Although it is not distinct of the mechanism, a plausible
reaction mechanism is proposed (Scheme 3) on the basis
of our results and previous findings[9]. With the assistance
(1a-1r) for nitration were prepared according to literature reported
]
methods[9, 10d,14,16
.
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In a three-necked flask (500 mL), 2-aminobenzonitrile (29.5 g, 250
mmol) and ZnCl2 (3.4 g, 25 mmol) were added, and then suspended in
chlorobenzene (350 mL) under nitrogen. 2-aminoethanol(45 mL, 750
mmol) was added to the suspension via a syringe. The mixture was
heated to reflux for 36 hours. After refluxing for 36 hours, the reaction
mixture was cooled down to room temperature and the solvent was
removed under reduced pressure. CH2Cl2 (250 mL) was added to the
residue and washed with saturated NaHCO3 (150 mL) and H2O (150 mL).
The aqueous fraction was extracted with CH2Cl2 (250 mL × 3). The
combined organic phase was dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was purified by
flash column chromatography (petroleum ether/ethyl acetate = 25/1) to
give 2-(4,5-dihydrooxazol-2-yl)aniline.
113.7, 66.3, 54.3. HRMS (ESI-QTOF) m/z Calcd for C16H12N4O6 [M+H]+
357.0835, found 357.0835.
N-(2-(4,5-dihydrooxazol-2-yl)phenyl)-2-nitro-6-
(trifluoromethyl)benzamide (2c): Following the general procedure the
title compound was synthesized at 60 °C for 12 h. Purified by flash
column chromatography on silica gel (petroleum ether/ethyl acetate =
12/1). Yellow solid (32 mg, 84%), mp: 174-175 °C. 1H NMR (300 MHz,
CDCl3) δ 12.78 (s, 1H), 8.74 (d, J = 8.3 Hz, 1H), 8.34 (d, J = 8.3 Hz, 1H),
8.04 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.74 (t, J = 8.1 Hz, 1H),
7.53 (t, J = 7.4 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 4.32 (t, J = 9.5 Hz, 2H),
3.91 (t, J = 9.3 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 164.0, 160.7, 146.8,
142.0, 138.6, 132.2, 131.2 (q, JC-F = 4.6 Hz), 129.8, 129.4 (d, JC-F = 33.0
Hz), 128.6, 127.6, 122.9, 122.1 (d, JC-F = 273.3 Hz), 119.9, 113.2, 65.8,
2-(4,5-dihydrooxazol-2-yl)aniline (5 mmol) and acid chloride (5.5 mmol) 53.9. HRMS (ESI-QTOF) m/z Calcd for C17H12F3N3O4 [M+H]+ 380.0858,
were added to a 100 mL flask and then dissolved with THF (20 mL). Et3N
(7.5 mmol) was taken to the vigorously stirred solution via a syringe. The
reaction was stirred at room temperature for 10 h and quenched with
saturated NaHCO3. And then the mixture was extracted with EtOAc.
Combined organic phase was washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The crude product
was purified by flash column chromatography (petroleum ether/ethyl
acetate) to give the substrates.
found 380.0856.
N-(2-(4,5-dihydrooxazol-2-yl)phenyl)-2-fluoro-6-nitrobenzamide (2d):
Following the general procedure the title compound was synthesized at
60 °C for 12 h. Purified by flash column chromatography on silica gel
(petroleum ether/ethyl acetate = 8/1). Yellow solid (31 mg, 94%), mp:
162-163 °C. 1H NMR (300 MHz, CDCl3) δ 12.84 (s, 1H), 8.83 (d, J = 7.6
Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.66–7.45 (m,
3H), 7.19 (t, J = 7.2 Hz, 1H), 4.36 (t, J = 9.1 Hz, 2H), 4.00 (t, J = 9.4 Hz,
2H). 13C NMR (75 MHz, CDCl3) δ 164.6, 159.4, 159.3 (d, JC-F = 251.6 Hz),
General Procedure for Cu(II)-Mediated ortho-C−H Nitration of
Arenes: An oven dried 25 mL two-necked flask, equipped with a stir bar,
was charge with substrates 1a-1r (0.1 mmol, 1 equiv), Cu(OAc)2 (0.2
mmol, 2 equiv), NaNO2 (0.3 mmol, 3 equiv) and DMSO (1 mL). Then
reaction mixture was stirred at 50~70 °C under oxygen for 1.5~12 h.
Upon completion, EtOAc was added to dilute the mixture and then
washed with NH3•H2O and H2O. The organic fraction was dried over
Na2SO4, evaporated and purified by flash column chromatography on
silica gel with a gradient eluent of petroleum ether/ethyl acetate to give
the nitration product 2a-2r.
147.1, 139.2, 132.7, 130.9 (d, JC-F = 8.6 Hz), 129.2, 123.3, 121.9 (d, JC-F
=
22.4 Hz), 120.4, 120.4, 120.3, 113.7, 66.3, 54.5. HRMS (ESI-QTOF) m/z
Calcd for C16H12FN3O4 [M+H]+ 330.0890, found 330.0888.
2-chloro-N-(2-(4,5-dihydrooxazol-2-yl)phenyl)-6-nitrobenzamide (2e):
Following the general procedure the title compound was synthesized at
60 °C for 5 h. Purified by flash column chromatography on silica gel
(petroleum ether/ethyl acetate = 8/1). Yellow solid (16 mg, 46%), mp:
179-180 °C. 1H NMR (300 MHz, CDCl3) δ 12.71 (s, 1H), 8.80 (d, J = 8.2
Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 8.1
N-(2-(4,5-dihydrooxazol-2-yl)phenyl)-2-methyl-6-nitrobenzamide (2a): Hz, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.18 (t, J = 7.5 Hz, 1H), 4.35 (t, J = 9.4
Following the general procedure the title compound was synthesized at
60 °C for 12 h. Purified by flash column chromatography on silica gel
(petroleum ether/ethyl acetate = 8/1). Yellow solid (30 mg, 92%), mp:
163-164 °C. 1H NMR (300 MHz, CDCl3) δ 12.51 (s, 1H), 8.83 (d, J = 8.4
Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.64–7.41 (m,
3H), 7.16 (t, J = 7.4 Hz, 1H), 4.33 (t, J = 9.5 Hz, 2H), 3.94 (t, J = 9.6 Hz,
2H), 2.52 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 164.3, 164.1, 145.7, 138.9,
137.3, 135.7, 132.5, 132.2, 128.9, 128.7, 122.6, 121.6, 119.9, 113.2,
65.7, 54.0, 18.8. HRMS (ESI-QTOF) m/z Calcd for C17H15N3O4 [M+H]+
326.1141, found 326.1143.
Hz, 2H), 3.97 (t, J = 9.4 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 164.1,
161.2, 146.4, 138.6, 135.0, 133.1, 132.2, 132.1, 129.8, 128.7, 122.8,
122.6, 120.0, 113.3, 65.8, 54.0. HRMS (ESI-QTOF) m/z Calcd for
C16H12ClN3O4 [M+H]+ 346.0595, found 346.0592.
N-(2-(4,5-dihydrooxazol-2-yl)phenyl)-2,3-dimethyl-6-nitrobenzamide
(2g): Following the general procedure the title compound was
synthesized at 70 °C for 12 h. Purified by flash column chromatography
on silica gel (petroleum ether/ethyl acetate = 8/1). Yellow solid (28 mg,
83%), mp: 185-186 °C. 1H NMR (300 MHz, CDCl3) δ 12.46 (s, 1H), 8.86
(d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.57
(t, J = 7.8 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 4.34
(t, J = 9.5 Hz, 2H), 3.95 (t, J = 9.5 Hz, 2H), 2.42 (d, J = 9.1 Hz, 6H). 13C
NMR (75 MHz, CDCl3) δ 165.0, 164.1, 144.6, 143.7, 138.9, 135.4, 132.7,
132.1, 130.1, 128.7, 122.5, 121.5, 119.9, 113.2, 65.7, 54.0, 20.3, 16.0.
HRMS (ESI-QTOF) m/z Calcd for C18H17N3O4 [M+H]+ 340.1297, found
340.1296.
N-(2-(4,5-dihydrooxazol-2-yl)phenyl)-2,6-dinitrobenzamide
(2b):
Following the general procedure the title compound was synthesized at
60 °C for 1.5 h. Purified by flash column chromatography on silica gel
(petroleum ether/ethyl acetate = 5/1). Yellow solid (28.8 mg, 81%), mp:
195-196 °C. 1H NMR (300 MHz, CDCl3) δ 12.86 (s, 1H), 8.70 (d, J = 8.1
Hz, 1H), 8.43 (d, J = 8.2 Hz, 2H), 7.91 (d, J = 7.4 Hz, 1H), 7.82 (t, J = 8.2
Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 4.36 (t, J = 9.4
Hz, 2H), 3.96 (t, J = 9.5 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 164.8,
159.6, 147.5, 139.0, 132.8, 130.8, 129.5, 129.2, 128.3, 123.5, 120.6,
N-(2-(4,5-dihydrooxazol-2-yl)phenyl)-2-methyl-3,6-dinitrobenzamide
(2h): Following the general procedure the title compound was
synthesized at 70 °C for 12 h. Purified by flash column chromatography
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10.1002/ejoc.201900117
European Journal of Organic Chemistry
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on silica gel (petroleum ether/ethyl acetate = 15/1). Yellow solid (32 mg,
86%), mp: 184-185 °C. 1H NMR (300 MHz, CDCl3) δ 12.79 (s, 1H), 8.78
(d, J = 8.2 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.95 (dd, J = 15.9, 8.5 Hz,
2H), 7.59 (t, J = 7.7 Hz, 1H), 7.22 (t, J = 7.4 Hz, 1H), 4.38 (t, J = 9.4 Hz,
2H), 3.99 (t, J = 9.4 Hz, 2H), 2.63 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
164.8, 162.2, 153.4, 147.4, 138.8, 135.8, 132.8, 132.6, 129.3, 125.0,
123.7, 123.3, 120.4, 113.8, 66.4, 54.4, 16.1. HRMS (ESI-QTOF) m/z
Calcd for C17H14N4O6 [M+H]+ 371.0992, found 371.0986.
N-(2-(4,5-dihydrooxazol-2-yl)phenyl)-4-ethyl-2,6-dinitrobenzamide
(2n): Following the general procedure the title compound was
synthesized at 60 °C for 2 h. Purified by flash column chromatography on
silica gel (petroleum ether/ethyl acetate = 8/1). Yellow solid (25 mg, 65%),
mp: 207-208 °C. 1H NMR (300 MHz, CDCl3) δ 12.76 (s, 1H), 8.67 (d, J =
8.4 Hz, 1H), 8.21 (s, 2H), 7.86 (d, J = 7.9 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H),
7.16 (t, J = 7.1 Hz, 1H), 4.33 (t, J = 9.4 Hz, 2H), 3.93 (t, J = 9.6 Hz, 2H),
2.90 (q, J = 7.6 Hz, 2H), 1.38 (t, J = 7.6 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 164.8, 159.9, 148.3, 147.6, 139.1, 132.7, 129.1, 128.6, 125.9,
123.4, 120.6, 113.7, 66.3, 54.3, 28.4, 14.4. HRMS (ESI-QTOF) m/z
Calcd for C18H16N4O6 [M+H]+ 385.1148, found 385.1145.
N-(2-(4,5-dihydrooxazol-2-yl)phenyl)-2,4-dimethyl-6-nitrobenzamide
(2i): Following the general procedure the title compound was synthesized
at 70 °C for 12 h. Purified by flash column chromatography on silica gel
(petroleum ether/ethyl acetate = 12/1). Yellow solid (27.8 mg, 82%), mp:
197-198 °C. 1H NMR (300 MHz, CDCl3) δ 12.47 (s, 1H), 8.84 (d, J = 8.3
Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.83 (s, 1H), 7.55 (t, J = 7.3 Hz, 1H),
7.39 (s, 1H), 7.16 (t, J = 7.6 Hz, 1H), 4.34 (t, J = 9.6 Hz, 2H), 3.96 (t, J =
9.5 Hz, 2H), 2.48 (d, J = 6.5 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 164.5,
164.1, 145.7, 139.4, 139.0, 137.0, 136.3, 132.1, 129.9, 128.7, 122.4,
121.9, 119.8, 113.1, 65.7, 54.0, 20.5, 18.7. HRMS (ESI-QTOF) m/z
Calcd for C18H17N3O4 [M+H]+ 340.1297, found 340.1294.
4-(tert-butyl)-N-(2-(4,5-dihydrooxazol-2-yl)phenyl)-2,6-
dinitrobenzamide (2o): Following the general procedure the title
compound was synthesized at 60 °C for 2 h. Purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 15/1).
Yellow solid (28.6 mg, 69%), mp: 214-215 °C. 1H NMR (300 MHz, CDCl3)
δ 12.65 (s, 1H), 8.56 (d, J = 8.3 Hz, 1H), 8.26 (s, 2H), 7.76 (d, J = 7.9 Hz,
1H), 7.43 (t, J = 7.9 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 4.23 (t, J = 9.5 Hz,
2H), 3.84 (t, J = 9.5 Hz, 2H), 1.34 (s, 9H). 13C NMR (75 MHz, CDCl3) δ
164.8, 159.9, 155.8, 147.6, 139.1, 132.7, 129.1, 126.4, 125.7, 123.4,
120.7, 113.8, 66.3, 54.3, 35.8, 30.7. HRMS (ESI-QTOF) m/z Calcd for
C20H20N4O6 [M+H]+ 413.1461, found 413.1458.
4-chloro-N-(2-(4,5-dihydrooxazol-2-yl)phenyl)-2-fluoro-6-
nitrobenzamide (2j): Following the general procedure the title
compound was synthesized at 50 °C for 4 h. Purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 18/1).
Yellow solid (34 mg, 93%), mp: 166-167 °C. 1H NMR (300 MHz, CDCl3) δ
12.89 (s, 1H), 8.79 (d, J = 7.8 Hz, 1H), 7.99 (s, 1H), 7.91 (d, J = 6.9 Hz,
1H), 7.58–7.53 (m, 2H), 7.19 (t, J = 7.6 Hz, 1H), 4.37 (t, J = 9.1 Hz, 2H),
4.02 (d, J = 8.6 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 164.7, 159.2 (d, JC-
N-(2-(4,5-dihydrooxazol-2-yl)phenyl)-4-fluoro-2,6-dinitrobenzamide
(2p): Following the general procedure the title compound was
synthesized at 50 °C for 1.5 h. Purified by flash column chromatography
on silica gel (petroleum ether/ethyl acetate = 12/1). Yellow solid (24 mg,
64%), mp: 205-206 °C. 1H NMR (300 MHz, CDCl3) δ 12.85 (s, 1H), 8.64
F = 254.9 Hz), 158.4, 139.0, 136.6 (d, JC-F = 10.9 Hz), 132.7, 129.2, 123.5, (d, J = 8.4 Hz, 1H), 8.13 (d, J = 7.1 Hz, 2H), 7.87 (d, J = 7.8 Hz, 1H), 7.54
122.3 (d, JC-F = 24.6 Hz), 121.1, 121.0 (d, JC-F = 3.4 Hz), 120.8, 120.3,
113.7, 66.3, 54.5. HRMS (ESI-QTOF) m/z Calcd for C16H11ClFN3O4
[M+H]+ 364.0500, found 364.0496.
(t, J = 7.7 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 4.33 (t, J = 9.5 Hz, 2H), 3.92
(t, J = 9.5 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 164.8, 161.2 (d, JC-F
=
257.8 Hz), 158.6, 148.5 (d, JC-F = 8.1 Hz), 138.9, 132.8, 129.2, 124.8,
123.6, 120.5, 117.6 (d, JC-F = 25.9 Hz), 113.7, 66.4, 54.3. HRMS (ESI-
QTOF) m/z Calcd for C16H11FN4O6 [M+H]+ 375.0741, found 375.0735.
4-chloro-N-(2-(4,5-dihydrooxazol-2-yl)phenyl)-2,6-dinitrobenzamide
(2k'): Following the general procedure the title compound was
synthesized at 50 °C for 1.5 h. Purified by flash column chromatography
on silica gel (petroleum ether/ethyl acetate = 10/1). Yellow solid (36 mg,
92%), mp: 220-221 °C. 1H NMR (300 MHz, CDCl3) δ 12.88 (s, 1H), 8.64
(d, J = 8.1 Hz, 1H), 8.38 (s, 2H), 7.88 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 7.3
Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 4.34 (t, J = 9.3 Hz, 2H), 3.94 (t, J = 9.3
Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 164.9, 158.6, 148.0, 138.8, 136.8,
132.8, 129.6, 129.2, 126.6, 123.7, 120.6, 113.7, 66.4, 54.3. HRMS (ESI-
QTOF) m/z Calcd for C16H11ClN4O6 [M+H]+ 391.0445, found 391.0437.
N-(2-(4,5-dihydrooxazol-2-yl)phenyl)-5-methyl-2-nitrobenzamide (2q-
1): Following the general procedure the title compound was synthesized
at 60 °C for 3 h. Purified by flash column chromatography on silica gel
(petroleum ether/ethyl acetate = 8/1). Yellow solid (8.5 mg, 26%), mp:
178-179 °C. 1H NMR (300 MHz, CDCl3) δ 12.69 (s, 1H), 8.81 (d, J = 8.3
Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 6.5 Hz, 1H), 7.61–7.43 (m,
2H), 7.38 (d, J = 8.5 Hz, 1H), 7.14 (t, J = 7.3 Hz, 1H), 4.35 (t, J = 9.4 Hz,
2H), 3.99 (t, J = 9.5 Hz, 2H), 2.49 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
164.8, 145.0, 144.8, 139.5, 133.4, 132.7, 131.0, 129.6, 129.2, 124.7,
123.0, 120.1, 113.6, 66.3, 54.4, 21.5. HRMS (ESI-QTOF) m/z Calcd for
C17H15N3O4 [M+H]+ 326.1141, found 326.1138.
N-(2-(4,5-dihydrooxazol-2-yl)phenyl)-4-methyl-2,6-dinitrobenzamide
(2m): Following the general procedure the title compound was
synthesized at 60 °C for 1.5 h. Purified by flash column chromatography
on silica gel (petroleum ether/ethyl acetate = 5/1). Yellow solid (24.8 mg,
67%), mp: 232-233 °C. 1H NMR (300 MHz, CDCl3) δ 12.67 (s, 1H), 8.57
(d, J = 8.1 Hz, 1H), 8.09 (s, 2H), 7.76 (d, J = 7.9 Hz, 1H), 7.43 (t, J = 8.0
Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 4.22 (t, J = 9.5 Hz, 2H), 3.82 (t, J = 9.5
Hz, 2H), 2.51 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 164.8, 159.8, 147.5,
142.3, 139.1, 132.7, 129.7, 129.1, 125.8, 123.4, 120.6, 113.7, 66.3, 54.3,
21.2. HRMS (ESI-QTOF) m/z Calcd for C17H14N4O6 [M+H]+ 371.0992,
found 371.0989.
N-(2-(4,5-dihydrooxazol-2-yl)phenyl)-3-methyl-2,6-dinitrobenzamide
(2q-2): Following the general procedure the title compound was
synthesized at 60 °C for 3 h. Purified by flash column chromatography on
silica gel (petroleum ether/ethyl acetate = 5/1). Yellow solid (11.7 mg,
32%), mp: 196-197 °C. 1H NMR (300 MHz, CDCl3) δ 12.94 (s, 1H), 8.65
(d, J = 8.4 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 7.4 Hz, 1H),
7.62–7.43 (m, 2H), 7.16 (t, J = 7.4 Hz, 1H), 4.35 (t, J = 9.5 Hz, 2H), 3.97
(t, J = 9.5 Hz, 2H), 2.51 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 164.7,
159.4, 149.4, 145.0, 138.9, 137.6, 133.1, 132.7, 129.1, 127.3, 126.4,
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10.1002/ejoc.201900117
European Journal of Organic Chemistry
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123.6, 120.4, 113.8, 66.4, 54.3, 18.5. HRMS (ESI-QTOF) m/z Calcd for
C17H14N4O6 [M+H]+ 371.0992, found 371.0989.
was purified by flash column chromatography (petroleum ether/ethyl
acetate = 25/1) to give product 3.
Gram-Scale reaction: To
a
250 mL two-necked flask was added
Nitration of compound 3: An oven dried 25 mL two-necked flask,
equipped with a stir bar, was charge with substrates 3 (0.1 mmol, 1
equiv), Cu(OAc)2 (0.2 mmol, 2 equiv), NaNO2 (0.3 mmol, 3 equiv) and
DMSO (1 mL). Then reaction mixture was stirred at 60 °C under oxygen
for 12 h. And there was no reaction proceeding.
substrates 1a (1.0 g, 3.6 mmol), Cu(OAc)2 (1308 mg, 7.2 mmol), NaNO2
(745 mg, 10.8 mmol) and DMSO (36 mL). Then reaction flask was placed
into a pre-heated oil bath and stirred at 60 °C under oxygen for 12 h.
Upon completion, EtOAc was added to dilute the mixture and then
washed with NH3•H2O and H2O. The organic fraction was dried over
Na2SO4, evaporated and purified by flash column chromatography on
silica gel (petroleum ether/ethyl acetate = 8/1) to afford the product with
78% yield (905 mg).
Acknowledgments
We are grateful to the fund supported by the Jiangsu
Provincial Natural Science Foundation (BK 20181333) and
Technology Innovation Team of Jiangsu Province in 2005
China.
Controlled Experiments
Intermolecular Competition Reaction Experiment: To a 25 mL two-
necked flask were added substrates 1l (0.05 mmol, 1 equiv), 1l-d5 (0.05
mmol, 1 equiv), Cu(OAc)2 (0.2 mmol, 2 equiv), NaNO2 (0.3 mmol, 3
equiv), DMSO (1 mL). Then reaction mixture was stirred at 60 °C under
oxygen for 1.5 h. Upon completion, EtOAc was added to dilute the
mixture and then washed with NH3·H2O and H2O. The organic fraction
was dried over Na2SO4, evaporated and a mixture of product 2l and 2l-d3
was purified by flash column chromatography on silica gel with a gradient
eluent of petroleum ether and ethyl acetate. The intermolecular kinetic
isotope effect was calculated to be kH/kD = 2.3 based on 1H NMR spectral
analyses.
Keywords: Copper • C-H activation • Nitro compounds •
Nitration • directing group
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Key Topic*
Tian-Hong Gao,[a] Chun-Meng Wang,[a]
Kai-Xiang Tang,[a] Yun-Gen Xu,[a] and Li-
Ping Sun*[a]
Page No. – Page No.
The first ortho-C-H nitration using amide-oxazoline as the directing group has been
reported. The reactions utilize simple and readily available nitro source and proceed
under Cu(II)-Mediated.
Amide-Oxazoline directed Ortho-C-H
Nitration under Cu(II)-Mediated
C-H Activation
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