Cu(II)-Catalyzed Ortho-C-H Nitration of Aryl Ureas by C-H Functionalization

Article abstract of DOI:10.1021/acs.joc.8b01016

A novel protocol for the aromatic ortho C-H nitration of aryl ureas with Fe(NO₃)₃·9H₂O is developed. The reaction utilizes CuCl₂·2H₂O as catalyst and p-TSA as additive, showing good functional group tolerance and furnishing the desired products in moderate to excellent yields.

Full text of DOI:10.1021/acs.joc.8b01016

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Article
Cu(II)-Catalyzed Ortho C-H Nitration of Aryl Ureas By C-H Functionalization
Chun-Meng Wang, Kai-Xiang Tang, Tian-Hong Gao, Lin Chen, and Li-Ping Sun
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01016 • Publication Date (Web): 03 Jul 2018
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Page 1 of 8
The Journal of Organic Chemistry
Cu(II)ꢀCatalyzed Ortho CꢀH Nitration of Aryl Ureas By CꢀH Funcꢀ
tionalization
1
2
3
4
5
ChunꢀMeng Wang, KaiꢀXiang Tang, TianꢀHong Gao, Lin Chen, LiꢀPing Sun*
6
7
Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical Uniꢀ
versity, Nanjing 210009, P. R. China
8
9
H
R2
N
NO2
R2
N
H
H
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N
N
CuCl 2H O, p-TSA
R3
R3
•
2
2
R1
R1
Fe(NO ) 9H O
•
+
3 3
2
toluene, 110 oC
O
O
17 examples, up to 92% yield
gram scale
ABSTRACT: A novel protocol for the aromatic ortho CꢀH nitration of aryl ureas with Fe(NO3)3·9H2O is developed. The reaction
utilizes CuCl2·2H2O as catalyst and pꢀTSA as additive, showing good functional group tolerance and furnishing the desired prodꢀ
ucts in moderate to excellent yields.
Introduction
for their preparation have been developed. In these methods,
the electrophilic nitration of arenes have long been the classic
and practical synthetic approach. However, the poor selectiviꢀ
ty and imperfect functional group tolerance restrict their appliꢀ
ance7. To overcome these drawbacks, several approaches have
been explored including the nitration of aryl halides, pseudoꢀ
halides, and organometallic compounds8. However, they still
suffer from the requirement of prefunctionalized substrate
precursors. The direct transformations of C−H bond to C−NO2
bond have drawn the attention because they could improve the
atom economy and simplify the operation. In the past decades,
transitionꢀmetalꢀcatalyzed chelation assisted C−H functionaliꢀ
zation have been widely explored and extensively employed in
organic synthesis. In 2010, Xu and Liu9a reported the first exꢀ
ample of a palladiumꢀcatalyzed direct orthoꢀnitration of aryl
CꢀH bonds by using azaarenes as the directing functional
groups. Since then, the chelationꢀdirected strategy was exꢀ
plored by using transition metals such as palladium9, copper10,
ruthenium11 and so on12 with various nitro sources. Despite the
advances, most of these reactions suffered from the use of Nꢀ
heterocycles as the directing groups, which are difficult to be
removed, thus having some limitation in substrate scopes.
Besides, some of them need harsh reaction conditions which
hamper the further application. Therefore, an easily available
nitro source, convenient reaction conditions and good regioseꢀ
lectivity are still the longꢀstanding goal for the nitration. Hereꢀ
in, we report the orthoꢀC−H nitration of ureas by using ureas
as the directing groups, which proceeds under convenient conꢀ
ditions in the presence of CuCl2·2H2O as catalyst with
Fe(NO3)3·9H2O utilized as nitro source.
Urea derivatives are widely used in many roles, includꢀ
ing those used as biologically active compounds, as pharmaꢀ
ceuticals, as agricultural pesticides and as antioxidants in
gasoline1 (Figure 1). Additionally, urea derivatives are also
important units in organic synthesis. A quite important appliꢀ
cation of them is served as excellent orthoꢀdirecting functional
groups in the activation of CꢀH bonds by transition metal cataꢀ
lysts. With their utilization, methods have been established for
the implementation of direct ortho CꢀC bond formation such
as arylation2, carbonylation3, alkenylation4 and other reacꢀ
tions5. However, in comparison with the wellꢀestablished cheꢀ
lationꢀassisted transition metal catalyzed C−C bond formation,
the direct C−N bond formation by using ureas as directing
groups is unknown.
O
CH3
HN
N
N
H
H
N
N
N
H
O
CH3
S
Antiarrhythmic drug
Signal transduction modulators
N
OCF3
HN
O
O
N
H
N
H
H3CO
N
N
N
H
H
N
N
N
P2Y1 antagonist
ROCK inhibitor
Results and Discussion
Figure 1. Bioactive compounds containing urea scaffolds exꢀ
amples.
In our initial investigation, the reaction was performed by
using N, NꢀdimethylꢀN’ꢀ(4ꢀmethylphenyl)urea (1a) as a model
substrate with CuCl2·2H2O (0.4 equiv), Fe(NO3)3·9H2O (0.35
equiv) and pꢀTSA (1 equiv) in 1,2ꢀdichloroethane (DCE) at 80
oC under air. To our delight, the reaction occurred at the orthoꢀ
position of the Nꢀaryl ring and gave product 2a in 77% yield
(Table 1，entry 1). Sequentially, we conducted the reaction
under O2 atmosphere and N2 atmosphere, respectively, to exꢀ
Aromatic nitro compounds are widely used as raw mateꢀ
rials in many disciplines of the chemical industry and also are
essential constituents in some therapeutic and pharmaceuticalꢀ
ly relevant molecules6. Up to now, numerous useful methods
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plore whether the atmosphere was able to improve the yield of
the product. However, the yields were not increased (entries 2ꢀ
3). Then additives were taken into consideration. Some other
Page 2 of 8
not lead to the formation of 2a in a drastically decreased yield
(entry 18). However, the yield decreased to 74% when the
amount of pꢀTSA was controlled to 0.5 equiv (entry 19). Fiꢀ
nally, the standard reaction conditions for the synthesis was
identified as follows: 0.2 equiv CuCl2·2H2O as the catalyst,
0.35 equiv Fe(NO3)3·9H2O as the nitro source, 1 equiv pꢀTSA
as the additive and toluene as the solvent under an air atmosꢀ
phere at 110 oC.
1
2
3
4
5
6
7
8
Table 1. Optimization Studies for the CuꢀCatalyzed Nitraꢀ
tion of Ureasa
Scheme 1. Substrate Scope of the Nitrationa
9
entry
1
catalyst
nitro source
additive
pꢀTSA
pꢀTSA
pꢀTSA
HOAc
TFA
solvent
DCE
yield(%)b
77
10
11
12
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60
.
.
CuCl2 2H2O
Fe(NO3)3 9H2O
.
.
2
CuCl2 2H2O
Fe(NO3)3 9H2O
DCE
78c
52d
60
NO2
NO2
NO2
H
H
H
.
.
3
CuCl2 2H2O
Fe(NO3)3 9H2O
DCE
N
N
N
N
N
N
.
.
O
O
O
4
CuCl2 2H2O
Fe(NO3)3 9H2O
DCE
Cl
F
Br
2b, 63%b
2d, 68%
2c, 66%
.
.
5
CuCl2 2H2O
Fe(NO3)3 9H2O
DCE
80
NO2
H
NO2
H
NO2
H
.
.
6
CuCl2 2H2O
Fe(NO3)3 9H2O
TfOH
PivOH
pꢀTSA
pꢀTSA
pꢀTSA
pꢀTSA
pꢀTSA
pꢀTSA
pꢀTSA
pꢀTSA
pꢀTSA
pꢀTSA
pꢀTSA
pꢀTSA
DCE
80
N
N
N
N
N
N
N
N
.
.
7
CuCl2 2H2O
Fe(NO3)3 9H2O
DCE
68
O
O
O
O
O
I
H3CO
2g, 92%
2e, 65%
2f, 60%
.
.
8
CuCl2 2H2O
Cu(NO3)2 3H2O
DCE
57
NO2
H
NO2
H
NO2
H
.
9
CuCl2 2H2O
AgNO2
DCE
N.D.e
89
N
N
N
N
N
N
.
.
10
11
12
13
14
15
16
17
18
19
CuCl2 2H2O
Fe(NO3)3 9H2O
toluene
CH3CN
THF
O
O
H3COOC
F3C
OCH3
2j, 50%
2i, 38%
2h, 35%
.
.
CuCl2 2H2O
Fe(NO3)3 9H2O
54
NO2
H
NO2
H
NO2
.
.
CuCl2 2H2O
Fe(NO3)3 9H2O
60
H
N
N
N
N
N
.
CuBr2
Fe(NO3)3 9H2O
toluene
toluene
toluene
toluene
toluene
toluene
toluene
84
O
O
O
H3CO
H3CO
Br
Cl
.
OCH3
OCH3
OCH3
Cu(OTf)2
Fe(NO3)3 9H2O
90
2m, 59%
2l, 55%
2k, 50%
.
.
Cu(OAc)2 H2O
Fe(NO3)3 9H2O
88
NO2
H
NO2
H
NO2
H
N
N
N
N
N
.
.
Cu(NO3)2 3H2O
Fe(NO3)3 9H2O
78
O
O
O
O
.
Cl
N.D.e
84f
F
ꢀꢀ
Fe(NO3)3 9H2O
Cl
2n, 33%
OCH3
2o, N.D.c
2p, trace
.
CuCl2.2H2O
CuCl2.2H2O
Fe(NO3)3 9H2O
NO2
H
NO2
H
NO2
H
H
N
H
N
.
Fe(NO3)3 9H2O
74g
N
N
N
N
OCH3
H3C
O
aReaction conditions: N,NꢀdimethylꢀN’ꢀ(4ꢀmethylphenyl)urea
(1a) (0.11 mmol, 1 equiv), Fe(NO3)3·9H2O (0.0385 mmol,
0.35 equiv), Cu salt (0.044 mmol, 0.4 equiv), additive (0.11
mmol, 1 equiv), solvent (3 mL), reflux. bIsolated yield. cReacꢀ
tion was carried out under N2 using a N2 balloon assembly.
dReaction was carried out under O2 using a O2 balloon asꢀ
H3C
H3C
2s, 90%
2r, trace
2q, 78%
NO2
H
O
N
N
O
H3C
e
f
sembly. N.D. = not detected. CuCl2·2H2O (0.022 mmol, 0.2
equiv). gpꢀTSA(0.055mmol, 0.5equiv.)
2t, 87%
aReaction conditions: ureas
Fe(NO3)3·9H2O (0.0385 mmol, 0.35 equiv), CuCl2·2H2O
(0.022 mmol, 0.2 equiv), pꢀTSA (0.11 mmol, 1 equiv), toluene
(3 mL), reflux. bIsolated yield. cN.D. = not detected.
1 (0.11 mmol, 1 equiv),
acids such as HOAc, TFA, TfOH and PivOH were used, and
the best result of them was at the same level compared with pꢀ
TSA (entries 4ꢀ7). Next, among the nitro sources examined,
Fe(NO3)3·9H2O gave the best result, whereas Cu(NO3)2·3H2O
and AgNO2 afforded the target product in less than 60% yield
(entries 8ꢀ9). For the solvents, toluene was found to be the
optimum choice, which gave the highest yield (89%) at reflux
temperature (entries 10ꢀ12). Afterwards, a screening of copper
sources showed that no obviously increased yield was exhibitꢀ
ed (entries 13−16). Control experiment confirmed that no reꢀ
action was observed without the Cu source (entry 17). Addiꢀ
tionally, lowering the amount of the Cu source (20 mol %) did
With the optimized reaction conditions established, the
scope and functional groups compatibility of this protocol was
explored (Scheme 1). For the N,NꢀdimethylꢀN’ꢀarylureas, the
urea containing unsubstituted phenyl ring reacted smoothly to
form the product 2f in a yield of 60%. A substrate bearing an
electronꢀdonating functional group (1g) produced the product
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The Journal of Organic Chemistry
in excellent yield (2g), whereas 1j, 1k having orthoꢀmethoxy
limiting step of this transformation. Next, when phenyl dimeꢀ
thylcarbamate (4) was used as a substrate, the nitration product
5 was not obtained, indicating that the NH group of ureas is
indispensable for the regioselective nitration.
1
2
3
4
5
6
7
8
and metaꢀmethoxy substituents were less reactive giving the
products in less than 60% yield. Slightly electronꢀwithdrawing
groups furnished the desired products in moderate yields (2bꢀ
2e), which could offer platforms for further functionalization
as they contain halogens. The strong electronꢀwithdrawing
groups, –CF3 and –COOCH3, drastically decreased the yields
and the expected product 2h and 2i were obtained in 35% and
38% yields, respectively. Disubstituted substrates bearing
methoxy and bromo groups at the 3ꢀ and 4ꢀpositions provided
the products (2l and 2m) in good yields (55 and 59%). Beꢀ
sides, a disubstituted substrate bearing fluoro and chloro
groups at the 4ꢀ and 3ꢀpositions also provided the orthoꢀ
nitrated product (2n) in 33% yield. However, substrate that the
2ꢀ and 4ꢀpositions were occupied by chloro groups offered the
product in trace yield. Interestingly, when methoxy substituted
the 3ꢀ and 5ꢀpositions, the substrate (1o) did not give the corꢀ
responding product (2o).
Scheme 3. Control Experiments
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Next, we investigated the application of ureas equipped
with different alkyl substituents on the nitrogen atom. Changꢀ
ing the dimethylamino moiety to cyclic diamines had no influꢀ
ence on the reaction, and thereby piperidine and morpholine
urea derivatives reacted excellently to provide 2s and 2t in
90% and 87% yields. At the same time, ureas which were conꢀ
stituted by primary amines were also studied. We found that
Nꢀethyl urea could be transformed smoothly under the catalytꢀ
ic conditions to 2q. Nevertheless, Nꢀmethoxy urea was reꢀ
stricted to provide the product 2r.
Although details about the mechanism remained to be asꢀ
certained, on the basis of these observations and earlier preceꢀ
dents10d, a plausible mechanism for this reaction was depicted
in Scheme 4. The substrate 1 may first bind with CuCl2·2H2O
to give an intermediate 6 that may undergo reaction with
Fe(NO3)3·9H2O to afford the intermediate 7. The subsequent
intramolecular orthoꢀnitration via an aromatic electrophilic
substitution can give the intermediate 8, which can afford the
target product 2 and the hydrated CuCl2 to complete the cataꢀ
lytic cycle.
Scheme 2. Gram Scale Reaction and Nitroarenes
Transformation
Scheme 4. Proposed Catalytic Cycle
Given the operational simplicity of this method, we perꢀ
formed a gram scale reaction (Scheme 2, a), and the nitration
product was obtained in 60% yield. To demonstrate the utility
of this method, we carried out a few transformations using the
nitration products as starting materials. Hydrogenation of 2a
under Pd/C and H2 condition provided aniline in excellent
yield (Scheme 2, b), which could be conveniently converted to
other functional groups (e.g., Cl, Br, I, CN...) via Sandmeyer
reactions.
Conclusion
In summary, we have developed a novel and efficient
copperꢀcatalyzed, highly regioselective, direct C−H nitration
of ureas with iron nitrate as a nitro source by utilizing ureas as
directing groups. The present method tolerates a variety of
functional groups and allows the synthesis of diverse nitrated
urea derivatives in moderate to excellent yields. This therefore
represents an important extension of the chemistry of urea
compounds.
To gain insights into the reaction pathway, additional exꢀ
periments were performed. Radical scavenger TEMPO
(2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy) was added under the
standard reactions (Scheme 3, a) to figure out whether a radiꢀ
cal intermediate was involved in the reaction. Although the
yield was decreased, the reaction was not completely supꢀ
pressed, suggesting that a radical pathway might not be inꢀ
volved. Then we performed an intermolecular competition
experiment between an electronꢀrich substrate (1g) and elecꢀ
tronꢀdeficient substrate (1i) under the optimized conditions.
The products 2g and 2i were isolated in equal yields, which
indicated that C–H activation was not involved in the rateꢀ
Experimental Section
General Information
Unless otherwise noted, all chemical reagents were comꢀ
mercially purchased and used without further purification.
Analytical TLC was carried out by using preꢀ254 coated plates
and visualized with UV light. Melting points (uncorrected)
1
were determined on a RYꢀ1 MP apparatus. H and 13C NMR
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Page 4 of 8
spectra were recorded on a Bruker AVꢀ300 spectrometer at
20.4. HRMS (ESIꢀQTOF) m/z: [M + H]+ calcd for C10H13N3O3
224.1035; found 224.1033.
1
2
3
4
5
6
7
8
300 MHz and 75 MHz, respectively. Chemical shifts are reꢀ
ported 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 QꢀTOF highꢀresolution mass spectromeꢀ
ter. Flash column chromatography was performed over silica
gel 200ꢀ300 m.
3ꢀ(4ꢀfluoroꢀ2ꢀnitrophenyl)ꢀ1,1ꢀdimethylurea (2b): Eluꢀ
ent: petroleum ether: ethyl acetate (8:1). Yellow solid, 70 mg,
o
1
yield: 63%. mp: 99ꢀ100 C. H NMR (300 MHz, CDCl3) δ
9.96 (s, 1H), 8.63 (dd, J = 9.6, 5.4 Hz, 1H), 7.81 (dd, J = 8.4,
2.4 Hz, 1H), 7.19ꢀ7.31 (m, 1H), 3.02 (s, 6H). 13C NMR (75
MHz, CDCl3) δ 155.8 (d, J = 243.7 Hz), 154.6, 134.1 (d, J =
2.3 Hz), 123.8 (d, J = 22 Hz), 123.2 (d, J = 7 Hz), 111.7 (d, J =
27 Hz), 36.4. HRMS (ESIꢀQTOF) m/z: [M + H]+ calcd for
C9H10FN3O3 228.0784; found 228.0779.
General Procedure for the Substrates 1aꢀ1t
9
All the starting substrates (1aꢀ1t) for nitration were preꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
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33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
pared according to literature reported methods4c, 5a
.
3ꢀ(4ꢀchloroꢀ2ꢀnitrophenyl)ꢀ1,1ꢀdimethylurea (2c): Eluꢀ
ent: petroleum ether: ethyl acetate (8:1). Yellow solid, 22 mg,
Method a: aniline derivatives (500 mg, 4.67 mmol) and
triethylamine (1.3 mL, 9.34 mmol) were dissolved in a two
neck round bottom flask followed by drop wise addition of
chlorofomic acid dimethyl amide (1.8 mL, 20 mmol) using a
syringe. The reaction mixture was stirred at room temperature.
After completion, the reaction was diluted with DCM (30
mL), washed by 2N HCl (15×3 mL), brine (15×3 mL). After
being dried over Na2SO4, the organic solvent was removed by
evaporation. Then the crude mixture was purified by flash
column chromatography (DCM/EA 50:1) to give 1aꢀ1q.
o
1
yield: 61%. mp: 95ꢀ96 C. H NMR (300 MHz, CDCl3) δ
10.15 (s, 1H), 8.73 (d, J = 9.3 Hz, 1H), 8.21 (t, J = 2.2 Hz, 1H),
7.57 (dd, J = 2.3, 9.3 Hz, 1H), 3.13 (s, 6H). 13C NMR (75
MHz, CDCl3) δ 154.3, 136.2, 136.0, 135.5, 126.3, 125.1,
122.6, 36.5. HRMS (ESIꢀQTOF) m/z: [M + H]+ calcd for
C9H10ClN3O3 244.0489; found 244.0481.
3ꢀ(4ꢀbromoꢀ2ꢀnitrophenyl)ꢀ1,1ꢀdimethylurea (2d): Elꢀ
uent: petroleum ether: ethyl acetate (8:1). Yellow solid, 54 mg,
o
1
yield: 76%. mp: 103ꢀ105 C. H NMR (300 MHz, CDCl3) δ
10.16 (s, 1H), 8.68 (d, J = 9.2 Hz, 1H), 8.36 (t, J = 2.3 Hz, 1H),
7.70 (dd, J = 2.2, 9.2 Hz, 1H), 3.13 (s, 6H). 13C NMR (75
MHz, CDCl3) δ 154.3, 138.8, 136.6, 135.7, 128.0, 122.8,
113.1, 36.5. HRMS (ESIꢀQTOF) m/z [M + H]+ calcd for
C9H10BrN3O3 287.9984; found 287.9977.
Method b: a solution of triphosgene (0.59 g, 2 mmol) in
dry DCM (10 mL) was prepared under an N2 atmosphere in a
two neck dried roundꢀbottom flask and cooled to 0 °C. A soluꢀ
tion of aryl amine (5.0 mmol) and triethylamine (1.38 mL, 10
mmol) in DCM (10 mL), which was prepared in a dried roundꢀ
bottom flask, was added slowly via cannula. After 15 minutes,
the ice bath was removed and the reaction mixture was alꢀ
lowed to stir at room temperature until the TLC analysis indiꢀ
cated conversion of the amine. In a separate dried flask, dry
triethylamine (1.52 mL, 11 mmol) was added under an N2
atmosphere to a solution of corresponding amine (5.5 mmol)
in dry DMF (10 mL) at room temperature. The resulting white
suspension was cooled to 0 °C and the solution containing the
isocyanate was added via cannula. The ice bath was removed
and the reaction mixture was stirred for 10ꢀ12 hours. The solꢀ
vent was removed under vacuum and the residue suspended in
DCM and filtered to remove the nonꢀsoluble triethylammoniꢀ
umchloride salt. Then 1qꢀ1t were obtained by flash column
chromatography (DCM/EA 50:1).
3ꢀ(4ꢀiodoꢀ2ꢀnitrophenyl)ꢀ1,1ꢀdimethylurea (2e): Eluent:
petroleum ether: ethyl acetate (8:1). Yellow solid, 68 mg, yield:
65%. mp: 145ꢀ146 oC. 1H NMR (300 MHz, CDCl3) δ 10.17 (s,
1H), 8.54 (d, J = 9.1 Hz, 2H), 7.86 (d, J = 8.3 Hz, 1H), 3.13 (s,
6H). 13C NMR (75 MHz, CDCl3) δ 154.2, 144.4, 137.2, 135.8,
133.9, 122.9, 82.2, 36.5. HRMS (ESIꢀQTOF) m/z [M + H]+
calcd for C9H10IN3O3 335.9845; found 335.9839.
1,1ꢀdimethylꢀ3ꢀ(2ꢀnitrophenyl)urea (2f): Eluent: petroꢀ
leum ether: ethyl acetate (8:1). Yellow solid, 69 mg, yield:
o
1
60%. mp: 78ꢀ79 C. H NMR (300 MHz, CDCl3) δ 10.2 (s,
1H), 8.69 (d, J = 8.6 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.60 (t,
J = 8.5, 7.3 Hz, 1H), 7.05 (t, J = 8.1, 7.6 Hz, 1H), 3.12 (s, 6H).
13C NMR (75 MHz, CDCl3) δ 154.6, 137.4, 136.0, 135.5,
125.7, 121.3, 36.4. HRMS (ESIꢀQTOF) m/z [M + H]+ calcd
for C9H11N3O3 210.0879; found 210.0874.
General Procedure for the Products 2aꢀ2t
To a mixture of substituted ureas 1 (0.25 mmol, 1 equiv.),
CuCl2·2H2O (0.05 mmol, 0.2 equiv.) and Fe(NO3)3·9H2O
(0.0875 mmol, 0.35 equiv) in toluene (3 mL) was added pꢀ
TSA (0.25 mmol, 1 equiv), then roundꢀbottom flask was
3ꢀ(4ꢀmethoxyꢀ2ꢀnitrophenyl)ꢀ1,1ꢀdimethylurea (2g):
Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 100
1
mg, yield: 92%. mp: 120ꢀ121 oC. H NMR (300 MHz, CDCl3)
δ 9.97 (s, 1H), 8.60 (d, J = 9.4 Hz, 1H), 7.65 (d, J = 2.6 Hz,
1H), 7.24 (dd, J = 2.7, 9.4 Hz, 1H), 3.85 (s, 3H), 3.11 (s, 6H).
13C NMR (75 MHz, CDCl3) δ 154.9, 153.6, 135.9, 131.6,
124.5, 123.0, 107.6, 55.8, 36.4. HRMS (ESIꢀQTOF) m/z [M +
H]+ calcd for C10H13N3O4 240.0984; found 240.0985.
o
stirred at 110 C temperature until TLC indicated the total
consumption of the ureas. Upon completion, the mixture was
treated with saturated NaHCO3 (10 mL) solution and extracted
with DCM (3 × 10 mL). The combined organic phase was
dried over Na2SO4 and then evaporated of the solvent under
reduced pressure. Next, purification of the crude residue by
flash column chromatography on silica gel (PE/EA) afforded
the desired products 2.
1,1ꢀdimethylꢀ3ꢀ(2ꢀnitroꢀ4ꢀ
(trifluoromethyl)phenyl)urea (2h): Eluent: petroleum ether:
ethyl acetate (8:1). Yellow solid, 25 mg, yield: 35%. mp:
o
1
above 300 C. H NMR (300 MHz, CDCl3) δ 10.27 (s, 1H),
8.80 (d, J = 8.9 Hz, 1H), 8.38 (s, 1H), 7.68 (d, J = 9.2 Hz, 1H),
3.02 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 154.0, 140.2, 134.4,
132.1 (d, J = 3.2 Hz), 124.8, 123.5 (t, J = 4.2 Hz), 122.1 (t, J =
138 Hz), 121.8, 36.5. HRMS (ESIꢀQTOF) m/z [M + H]+ calcd
for C10H10F3N3O3 278.0753; found 278.0749.
Characterization Data of Products 2
1,1ꢀdimethylꢀ3ꢀ(4ꢀmethylꢀ2ꢀnitrophenyl)urea (2a): Elꢀ
uent: petroleum ether: ethyl acetate (8:1). Yellow solid, 54 mg,
o
1
yield: 84%. mp: 102ꢀ103 C. H NMR (300 MHz, CDCl3) δ
10.10 (s, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.43 (d, J
= 8.3 Hz, 1H), 3.12 (s, 6H), 2.37 (s, 1H). 13C NMR (75 MHz,
CDCl3) δ 154.7, 137.1, 135.4, 135.1, 131.3, 125.3, 121.2, 36.4,
methyl 4ꢀ(3,3ꢀdimethylureido)ꢀ3ꢀnitrobenzoate (2i):
Eluent: petroleum ether: ethyl acetate (12:1). Yellow solid, 37
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The Journal of Organic Chemistry
mg, yield: 38%. mp: 152ꢀ153 oC. 1H NMR (300 MHz, CDCl3)
2.03(s, 4H). 13C NMR (75 MHz, CDCl3) δ 153.0, 137.1, 135.2,
134.7, 131.1, 125.2, 121.1, 45.9, 25.6, 20.4, 15.1. HRMS
(ESIꢀQTOF) m/z: [M + H]+ calcd for C12H15N3O3 250.1192;
found 250.1179.
1
2
3
4
5
6
7
8
δ 10.48 (s, 1H), 8.92 (s, 1H), 8.85 (d, J = 9.1 Hz, 1H), 8.23 (d,
J = 9.1 Hz, 1H), 3.96 (s, 3H), 3.16 (s, 6H). 13C NMR (75 MHz,
CDCl3) δ 165.0, 154.0, 140.8, 136.3, 127.8, 123.0, 120.7, 52.5,
36.5. HRMS (ESIꢀQTOF) m/z [M + H]+ calcd for C11H13N3O5
290.0753; found 290.0749.
Nꢀ(4ꢀmethylꢀ2ꢀnitrophenyl)morpholineꢀ4ꢀ
carboxamide (2t): Eluent: petroleum ether: ethyl acetate (4:1).
o
1
3ꢀ(2ꢀmethoxyꢀ6ꢀnitrophenyl)ꢀ1,1ꢀdimethylurea
(2j):
Yellow solid, 52 mg, yield: 87%, mp: 145ꢀ146 C. H NMR
(300 MHz, CDCl3) δ 10.14 (s, 1H), 8.52 (d, J = 8.7 Hz, 1H),
8.02 (s, 1H), 7.45 (d, J = 8.6 Hz, 1H), 3.79 (t, J = 4.5, 5.0 Hz,
3H), 3.59 (t, J = 4.5, 4.9 Hz, 3H), 2.38 (s, 3H). 13C NMR (75
MHz, CDCl3) δ 153.9, 137.2, 135.5, 134.7, 131.8, 125.4,
121.4, 66.5, 44.1, 20.4, 15.1. HRMS (ESIꢀQTOF) m/z: [M +
H]+ calcd for C12H15N3O4 266.1141; found 266.1130.
Eluent: petroleum ether: ethyl acetate (16:1). Yellow solid, 90
1
mg, yield: 50%. mp: 126ꢀ127 oC. H NMR (300 MHz, CDCl3)
δ 8.40 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.7 Hz, 2H), 7.71 (s,
1H), 7.38 (s, 1H), 3.98 (s, 3H), 3.07 (s, 6H). 13C NMR (75
MHz, CDCl3) δ 154.4, 146.6, 141.6, 118.1, 116.7, 104.9, 56.4,
36.4. HRMS (ESIꢀQTOF) m/z [M + H]+ calcd for C10H13N3O4
240.0984; found 240.0981.
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The Procedure for the Reduction of Compound 2a
3ꢀ(5ꢀmethoxyꢀ2ꢀnitrophenyl)ꢀ1,1ꢀdimethylurea (2k):
To a solution of compound 2a (100 mg, 0.446 mmol) in
MeOH (10 ml) was added 5% palladiumꢀcarbon catalyst (20
mg). The reaction mixture was allowed to stir at room temperꢀ
ature under H2. After 6 h, the mixture was filtered, concentratꢀ
ed in vacuo and purified by column chromatography (petroleꢀ
um ether: ethyl acetate 1:2) to give 74 mg (86%) of compound
3a as a purple solid.
Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 59
1
mg, yield: 50%. mp: 151ꢀ153 oC. H NMR (300 MHz, CDCl3)
δ 10.72 (s, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 9.6 Hz,
1H), 6.58 (dd, J = 2.3, 9.7 Hz, 1H), 3.93 (s, 3H), 3.14 (s, 6H).
13C NMR (75 MHz, CDCl3) δ 165.8, 154.8, 140.5, 128.7,
128.0, 110.2, 102.1, 56.0, 36.4. HRMS (ESIꢀQTOF) m/z: [M
+ H]+ calcd for C10H13N3O4 240.0984; found 240.0983.
The Data of Compound 3a
3ꢀ(4,5ꢀdimethoxyꢀ2ꢀnitrophenyl)ꢀ1,1ꢀdimethylurea (2l):
Eluent: petroleum ether: ethyl acetate (12:1). Yellow solid, 67
mg, yield: 55%, mp: 172ꢀ173 oC. 1H NMR (300 MHz, CDCl3)
δ 10.72 (s, 1H), 8.51 (s, 1H), 7.69 (s, 1H), 4.03 (s, 3H), 3.94 (s,
3H), 3.14 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 156.3, 155.0,
143.4, 135.2, 127.4, 106.7, 101.8, 56.6, 56.2, 36.4. HRMS
(ESIꢀQTOF) m/z: [M + H]+ calcd for C11H15N3O5 270.1090;
found 270.1086.
3ꢀ(2ꢀaminoꢀ4ꢀmethylphenyl)ꢀ1,1ꢀdimethylurea:
o
1
Purple solid, 74 mg, yield: 86%, mp: 42ꢀ43 C. H NMR
(300 MHz, CDCl3) δ 6.82 (d, J = 7.7 Hz, 1H), 6.49 (s, 1H),
6.47 (d, J = 7.7 Hz, 1H), 5.98 (s, 1H), 3.82 (s, 2H), 2.91 (s,
6H), 2.14 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 156.5, 141.5,
136.4, 125.7, 123.0, 120.2, 118.5, 36.6, 21.0. HRMS (ESIꢀ
QTOF) m/z: [M + H]+ calcd for C10H16N3O 194.1293; found
194.1284.
3ꢀ(4ꢀbromoꢀ5ꢀmethoxyꢀ2ꢀnitrophenyl)ꢀ1,1ꢀ
Controlled Experiments:
dimethylurea (2m): Eluent: petroleum ether: ethyl acetate
o
1
(8:1). Yellow solid, 35 mg, yield: 59%. mp: 159ꢀ160 C. H
NMR (300 MHz, CDCl3) δ 10.66 (s, 1H), 8.57 (s, 1H), 8.48 (s,
1H), 4.03 (s, 3H), 3.15 (s, 6H). 13C NMR (75 MHz, CDCl3) δ
161.8, 154.5, 139.6, 130.4, 128.8, 103.7, 101.7, 57.1, 36.5.
HRMS (ESIꢀQTOF) m/z: [M + H]+ calcd for C10H12BrN3O4
318.0089; found 318.0083.
Reaction in the Presence of Radical Quencher TEMPO
To a mixture of substituted ureas 1 (0.25 mmol, 1 equiv.),
CuCl2·2H2O (0.05 mmol, 0.2 equiv.), Fe(NO3)3·9H2O (0.0875
mmol, 0.35 equiv) and TEMPO (0.25 mmol, 1 equiv) in
toluene (3 mL) was added pꢀTSA (0.25 mmol, 1 equiv), then
o
roundꢀbottom flask was stirred at 110 C temperature. Upon
3ꢀ(3ꢀchloroꢀ4ꢀfluoroꢀ2ꢀnitrophenyl)ꢀ1,1ꢀdimethylurea
(2n): Eluent: petroleum ether: ethyl acetate (16:1). Yellow
solid, 20 mg, yield: 33%, mp: 145ꢀ146 oC. 1H NMR (300 MHz,
CDCl3) δ 10.14 (s, 1H), 8.96 (d, J = 7.1 Hz, 1H), 8.01 (d, J =
8.8 Hz, 1H), 3.11 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 154.2,
151.4 (d, J = 246 Hz), 134.4 (d, J = 2.7 Hz), 130.6 (d, J = 18
Hz), 122.8, 112.7 (d, J = 26 Hz), 36.4. HRMS (ESIꢀQTOF)
m/z: [M + H]+ calcd for C9H9ClFN3O3 262.0395; found
262.0390.
completion, the mixture was treated with saturated NaHCO3
(10 mL) solution and extracted with DCM (3 × 10 mL). The
combined organic phase was dried over Na2SO4 and then
evaporated of the solvent under reduced pressure. Next,
purification of the crude residue by flash column
chromatography on silica gel (petroleum ether: ethyl acetate
8:1) afforded the desired product 2a in a yield of 53%.
Intermolecular Competition Reaction between 1g and 1i
To a mixture of urea 1g (0.15 mmol), 1i (0.15 mmol),
CuCl2·2H2O (0.06 mmol, 0.2 equiv.) and Fe(NO3)3·9H2O
(0.105 mmol, 0.35 equiv) in toluene (3 mL) was added pꢀTSA
(0.3 mmol, 1 equiv), then roundꢀbottom flask was stirred at
110 oC temperature. Upon completion, the mixture was treated
with saturated NaHCO3 (10 mL) solution and extracted with
DCM (3 × 10 mL). The combined organic phase was dried
over Na2SO4 and then evaporated of the solvent under reduced
pressure. Next, the mixed products 2g and 2i were separate
through the purification of the crude residue with flash column
chromatography on silica gel (petroleum ether: ethyl acetate
1ꢀethylꢀ3ꢀ(4ꢀmethylꢀ2ꢀnitrophenyl)urea (2q): Eluent:
petroleum ether: ethyl acetate (6:1). Yellow solid, 49 mg, yield:
1
78%, mp: 170ꢀ171 oC. H NMR (300 MHz, CDCl3) δ 9.70 (s,
1H), 8.54 (d, J = 8.7 Hz, 1H), 7.99 (s, 1H), 7.43 (d, J = 8.6 Hz,
1H), 5.02 (s, 1H), 3.40ꢀ3.36 (m, 2H), 2.37 (s, 3H), 1.25 (t, J =
7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 154.3, 137.0, 135.2,
134.9, 131.3, 125.2, 121.5, 34.5, 20.3, 15.1. HRMS (ESIꢀ
QTOF) m/z: [M + H]+ calcd for C10H13N3O3 224.1035; found
224.1029.
Nꢀ(4ꢀmethylꢀ2ꢀnitrophenyl)pyrrolidineꢀ1ꢀcarboxamide
(2s): Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid,
1
8:1). The ratio of 2g and 2i was determined by HꢀNMR,
o
1
55 mg, yield: 90%, mp: 148ꢀ149 C. H NMR (300 MHz,
CDCl3) δ 9.96 (s, 1H), 8.65 (d, J = 8.7 Hz, 1H), 8.0 (s, 1H),
7.43 (d, J = 8.8 Hz, 1H), 3.58ꢀ3.54 (m, 4H), 2.37 (s, 3H),
which showed the result was 1:1.
The Preparation of Phenyl Dimethylcarbamate 4
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Page 6 of 8
(3) Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler,
The substrate 4 was prepared according to literature reꢀ
ported method13.
S. N.; Gagne, M. R.; LloydꢀJones, G. C.; BookerꢀMilburn, K. I.
RoomꢀTemperature PalladiumꢀCatalyzed CꢀH Activation: orthoꢀ
Carbonylation of Aniline Derivatives. Angew. Chem. Int. Ed.
2009, 48, 1830ꢀ1833.
1
2
3
4
5
6
7
8
The Nitration of Phenyl Dimethylcarbamate 4
To a mixture of compound 4 (41 mg, 0.25 mmol, 1
equiv.), CuCl2·2H2O (0.05 mmol, 0.2 equiv.) and
Fe(NO3)3·9H2O (0.0875 mmol, 0.35 equiv) in toluene (3 mL)
was added pꢀTSA (0.25 mmol, 1 equiv), then roundꢀbottom
flask was stirred at 110 oC temperature for 10 h and there was
no reaction proceeding.
(4) (a) Rauf, W.; Thompson, A. L.; Brown, J. M. Comparative
Catalytic CꢀH vs CꢀSi Activation of Arenes with Pd Complexes
Directed by Urea or Amide Groups. Chem. Commun.2009,
3874ꢀ3876. (b) Nishikata, T.; Lipshutz, B. H. Cationic Pd(II)ꢀ
Catalyzed Fujiwara−Moritani Reactions at Room Temperature
in Water. Org. Lett. 2010, 12, 1972ꢀ1975. (c) Willwacher, J.;
Rakshit, S.; Glorius, F. Investigating NꢀmethoxyꢀN'ꢀaryl Ureas
in Oxidative CꢀH Olefination Reactions: An Unexpected
Oxidation Behaviour. Org. Biomol. Chem. 2011, 9, 4736ꢀ4740.
(d) Jiang, P.; Xu, Y.; Sun, F.; Liu, X.; Li, F.; Yu, R.; Li, Y.;
9
ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website
Wang,
Q.
Pd(II)ꢀCatalyzed
orthoꢀCꢀH
Olefination/Dearomatization of NꢀAryl Ureas: An Approach to
Imine Derivatives. Org. Lett. 2016, 18, 1426ꢀ1429.
Copies of 1H and 13C NMR spectra
(5) (a) Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagné, M. R.;
LloydꢀJones, G. C.; BookerꢀMilburn, K. I. Distinct Reactivity of
AUTHOR INFORMATION
Pd(OTs)2:
The
Intermolecular
Pd(II)ꢀCatalyzed
1,2ꢀ
Corresponding Author
Carboamination of Dienes. J. Am. Chem. Soc. 2008, 130, 10066ꢀ
10067. (b) Huestis, M. P.; Chan, L.; Stuart, D. R.; Fagnou, K.
The Vinyl Moiety as A Handle for Regiocontrol in the
Preparation of Unsymmetrical 2,3ꢀAliphaticꢀSubstituted Indoles
and Pyrroles. Angew. Chem. Int. Ed. 2011, 50, 1338ꢀ1341. (c)
Kovács, S.; Tóth, B. L.; Borsik, G.; Bihari, T.; May, N. V.;
Stirling, A.; Novák, Z. Direct orthoꢀTrifluoroethylation of
Aromatic Ureas by Palladium Catalyzed CꢀH Activation: A
Missing Piece of Aromatic Substitutions. Adv. Synth. Catal.
2017, 359, 527ꢀ532.
* Email: chsunlp@163.com; chslp@cpu.edu.cn
ACKNOWLEDGMENT
We are grateful to the funds supported by the National Natural
Science Foundation (NO. 21472243), Jiangsu Provincial Natural
Science Foundation, the National College Students Innovation
Training Program and Technology Innovation Team of Jiangsu
Province in 2015 China.
(6) (a) Ono, N. The Nitro Group in Organic Synthesis; WileyꢀVCH:
New York, 2001. (b) Feuer, H.; Nielsen, A. T. Nitro
Compounds:Recent Advances in Synthesis and Chemistry;
WileyꢀVCH: New York, 1990.
(7) Olah, G. A.; Malhotra, R.; Narang, S. C. Nitration: Methods and
Mechanisms; WileyꢀVCH: Weinheim, 1989.
REFERENCES
(1) For selected examples, see: (a) Yin, Y.; Cameron, M. D.; Lin,
L.; Khan, S.; Schroter, T.; Grant, W.; Pocas, J.; Chen, Y.ꢀT.;
Schurer, S.; Pachori, A.; LoGrasso, P.; Feng, Y. Discovery of
Potent and Selective UreaꢀBased ROCK Inhibitors and Their Efꢀ
fects on Intraocular Pressure in Rats. ACS Med. Chem. Lett.
2010, 1, 175ꢀ179. (b) Qiao, J.ꢀX.; Wang, T.ꢀC.; Ruel, R.;
Thibeault, C.; L'Heureux, A.; Schumacher, W. A.; Spronk, S.
A.; Hiebert, S.; Bouthillier, G.; Lloyd, J.; Pi, Z.; Schnur, D. M.;
Abell, L. M.; Hua, J.; Price, L. A.; Liu, E.; Wu, Q.; Steinbacher,
T. E.; Bostwick, J. S.; Chang, M.; Zheng, J.; Gao, Q.; Ma, B.;
McDonnell, P. A.; Huang, C. S.; Rehfuss, R.; Wexler, R. R.;
Lam, P. Y. Conformationally Constrained orthoꢀanilino Diaryl
ureas: Discovery of 1ꢀ(2ꢀ(1'ꢀneopentylspiro[indolineꢀ3,4'ꢀ
piperidine]ꢀ1ꢀyl)phenyl)ꢀ3ꢀ(4ꢀ(trifluoromet hoxy)phenyl)Urea, a
Potent, Selective, and Bioavailable P2Y1 Antagonist. J. Med.
Chem. 2013, 56, 9275ꢀ9295. (c) Mainolfi, N.; Karki, R.; Liu, F.;
Anderson, K. Evolution of a New Class of VEGFRꢀ2 Inhibitors
from Scaffold Morphing and Redesign. ACS Med. Chem. Lett.
2016, 7, 363ꢀ367. (d) Zhang, H.ꢀQ.; Gong, F.ꢀH.; Ye, J.ꢀQ.;
Zhang, C.; Yue, X.ꢀH.; Li, C.ꢀG.; Xu, Y.ꢀG.; Sun, L.ꢀP. Design
and Discovery of 4ꢀanilinoquinazolineꢀurea Derivatives as Dual
TK Inhibitors of EGFR and VEGFRꢀ2. Eur. J. Med. Chem.
2017, 125, 245ꢀ254.
(2) (a) Nishikata, T.; Abela, A. R.; Huang, S.; Lipshutz, B. H. Catiꢀ
onic Palladium (II) Catalysis: C−H Activation/Suzuki−Miyaura
Couplings at Room Temperature. J. Am. Chem. Soc. 2010, 132,
4978ꢀ4979. (b) Nishikata, T.; Abela, A. R.; Lipshutz, B. H.,
Room Temperature CꢀH Activation and CrossꢀCoupling of Aryl
Ureas in Water. Angew. Chem. Int. Ed. 2010, 49, 781ꢀ784. (c)
Jiang, Z.; Zhang, L.; Dong, C.; Su, X.; Li, H.; Tang, W.; Xu, L.;
Fan, Q., Direct Synthesis of 8ꢀAryl tetrahydroquinolines via Pdꢀ
Catalyzed orthoꢀArylation of Aryl Ureas in Water. RSC
Advances 2013, 3, 1025ꢀ1028. (d) Jiang, P.; Li, F.; Xu, Y.; Liu,
Q.; Wang, J.; Ding, H.; Yu, R.; Wang, Q. Aromaticityꢀ
Dependent Regioselectivity in Pd(II)ꢀCatalyzed CꢀH Direct
Arylation of Aryl Ureas. Org. Lett. 2015, 17, 5918ꢀ5921.
(8) For selective examples, see: (a) Prakash, G. K. S.; Panja, C.;
Mathew, T.; Surampudi, V.; Petasis, N. A.; Olah, G. A. ipsoꢀ
Nitration
of
Arylboronic
Acids
with
Chlorotrimethylsilane−Nitrate Salts. Org. Lett. 2004, 6, 2205ꢀ
2207. (b) Saito, S.; Koizumi, Y. CopperꢀCatalyzed Coupling of
Aryl Halides and Nitrite Salts: A Mild Ullmannꢀtype Synthesis
of Aromatic Nitro Compounds. Tetrahedron Lett. 2005, 46,
4715ꢀ4717. (c) Fors, B. P.; Buchwald, S. L. PdꢀCatalyzed
Conversion of Aryl Chlorides, Triflates, and Nonaflates to
Nitroaromatics. J. Am. Chem. Soc. 2009, 131, 12898ꢀ12899. (d)
Prakash, G. K.; Mathew, T. ipsoꢀNitration of arenes. Angew.
Chem. Int. Ed. 2010, 49, 1726ꢀ1728.
(9) (a) Liu, Y.ꢀK.; Lou, S.ꢀJ.; Xu, D.ꢀQ.; Xu, Z.ꢀY. Regiospecific
Synthesis of Nitroarenes by PalladiumꢀCatalyzed Nitrogenꢀ
DonorꢀDirected Aromatic CꢀH Nitration. Chem. ꢀEur. J. 2010,
16, 13590ꢀ13593. (b) Zhang, W.; Lou, S.; Liu, Y.; Xu, Z.
PalladiumꢀCatalyzed ChelationꢀAssisted Aromatic C–H
Nitration: Regiospecific Synthesis of Nitroarenes Free from the
Effect of the Orientation Rules. J. Org. Chem. 2013, 78, 5932ꢀ
5948. (c) Zhang, W.; Zhang, J.; Ren, S.; Liu, Y. Palladiumꢀ
Catalyzed Aromatic CꢀH Bond Nitration Using Removable
Directing Groups: Regiospecific Synthesis of Substituted oꢀ
Nitrophenols from Related Phenols. J. Org. Chem. 2014, 79,
11508ꢀ11516. (d) Dong, J.; Jin, B.; Sun, P. PalladiumꢀCatalyzed
Direct orthoꢀNitration of Azoarenes Using NO2 as Nitro Source.
Org. Lett. 2014, 16, 4540ꢀ4542. (e) Liang, Y.ꢀF.; Li, X.; Wang,
X.; Yan, Y.; Feng, P.; Jiao, N. Aerobic Oxidation of PdII to
PdIV by Active Radical Reactants: Direct C–H Nitration and
Acylation of Arenes via Oxygenation Process with Molecular
Oxygen. ACS Catalysis 2015, 5, 1956ꢀ1963. (f) Qiao, H.ꢀJ.;
Yang, F.; Wang, S.ꢀW.; Leng, Y.ꢀT.; Wu, Y.ꢀJ. Palladiumꢀ
catalyzed orthoꢀnitration of 2ꢀarylbenzoxazoles. Tetrahedron
2015, 71, 9258ꢀ9263. (g) Pawar, G. G.; Brahmanandan, A.;
Kapur, M. Palladium(II)ꢀCatalyzed, HeteroatomꢀDirected,
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Page 7 of 8
The Journal of Organic Chemistry
Regioselective CꢀH Nitration of Anilines Using Pyrimidine as a
Removable Directing Group. Org. Lett. 2016, 18, 448ꢀ451.
(10) (a) Zhang, L.; Liu, Z.; Li, H.; Fang, G.; Barry, B. D.; Belay, T.
A.; Bi, X.; Liu, Q. CopperꢀMediated ChelationꢀAssisted Ortho
Nitration of (Hetero)arenes. Org. Lett. 2011, 13, 6535ꢀ6539. (b)
Katayev, D.; Pfister, K. P.; Wendling, T.; Gooßen, L. J. Copperꢀ
Mediated orthoꢀNitration of (Hetero)Arenecarboxylates.
Chem.−Eur. J. 2014, 20, 9902ꢀ9905. (c) Elier, H.; R., C. R.;
Nuria, R.; Ramón, G. A.; C., C. J. CopperꢀCatalyzed Mild
Nitration of Protected Anilines. Chem.−Eur. J. 2014, 20, 13854ꢀ
13859. (d) Sadhu, P.; Alla, S. K.; Punniyamurthy, T. Roomꢀ
Temperature Cu(II)ꢀcatalyzed Chemoꢀ and Regioselective orthoꢀ
Nitration of Arenes via CꢀH Functionalization. J. Org. Chem.
2015, 80, 8245ꢀ8253. (e) Liu, J.ꢀD.; Zhuang, S.ꢀB.; Gui, QꢀW.;
Chen, X.; Yang, Z.ꢀY.; Tan, Z. CopperꢀMediated orthoꢀNitration
of Arene and Heteroarene CꢀH Bonds Assisted by An 8ꢀ
Aminoquinoline Directing Group. Adv. Synth. Catal. 2015, 357,
732ꢀ738. (f) Ji, Y.ꢀF.; Yan, H.; Jiang, Q.ꢀB. Effective Nitration
of Anilides and Acrylamides by tertꢀButyl Nitrite. Eur. J. Org.
Chem. 2015, 2015, 2051ꢀ2060. (g) Zhu, X.; Qiao, L.; Ye, P.;
Ying, B.; Xu, J.; Shen, C.; Zhang, P. CopperꢀCatalyzed Rapid
C–H Nitration of 8ꢀAminoquinolines by Using Sodium Nitrite as
the Nitro Source under Mild Conditions. RSC Advances 2016, 6,
89979ꢀ89983. (h) Vinayak, B.; Ashok, A.; Chandrasekharam,
M. CopperꢀCatalyzed ChelationꢀAssisted orthoꢀNitration of 2ꢀ
Aryls Using Pharmacophoric Benzothiazoles and Benzoxazoles
as Directing Groups. Eur. J. Org. Chem. 2017, 2017, 7127ꢀ7132.
(i) Vinayak, B.; Chandrasekharam, M. CopperꢀCatalyzed Direct
Nitration on Aryl CꢀH Bonds by Concomitant Azidationꢀ
Oxidation with TMS Azide and TBHP under Aerobic
Conditions. Org. Lett. 2017, 19, 3528ꢀ3531.
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5
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54
55
56
57
58
59
60
(11) (a) Fan, Z.; Ni, J.; Zhang, A. MetaꢀSelective CArꢀH Nitration of
Arenes through
a
Ru3(CO)12ꢀCatalyzed OrthoꢀMetalation
Strategy. J. Am. Chem. Soc. 2016, 138, 8470ꢀ8475. (b) Fan, Z.;
Li, J.; Lu, H.; Wang, D. Y.; Wang, C.; Uchiyama, M.; Zhang, A.
Monomeric Octahedral Ruthenium(II) Complex Enabled metaꢀ
CꢀH Nitration of Arenes with Removable Auxiliaries. Org. Lett.
2017, 19, 3199ꢀ3202. (c) Fan, Z.; Lu, H.; Zhang, A. PMes3ꢀ
Promoted RutheniumꢀCatalyzed Meta CꢀH Nitration of 6ꢀ
Arylpurines. J. Org. Chem. 2018, 83, 3245ꢀ3251.
(12) (a) Xie, F.; Qi, Z.; Li, X. Rhodium(III)ꢀCatalyzed Azidation and
Nitration of Arenes by CꢀH Activation. Angew. Chem. Int. Ed.
2013, 52, 11862ꢀ11866. (b) Whiteoak, C. J.; Planas, O.;
Company, A.; Ribas, X. A First Example of CobaltꢀCatalyzed
Remote CꢀH Functionalization of 8ꢀAminoquinolines Operating
through A Single Electron Transfer Mechanism. Adv. Synth.
Catal. 2016, 358, 1679ꢀ1688. (c) He, Y.; Zhao, N.; Qiu, L.;
Zhang, X.; Fan, X. Regioꢀ and Chemoselective Monoꢀ and
.
Bisnitration of 8ꢀAmino quinoline Amides with Fe(NO3)3 9H2O
as Promoter and Nitro Source. Org. Lett. 2016, 18, 6054ꢀ6057.
(d) Wang, Y.; Yu, F.; Han, X.; Li, M.; Tong, Y.; Ding, J.; Hou,
H. From Surprising Solvothermal Reaction to Uncommon
Zinc(II)ꢀCatalyzed Aromatic CꢀH Activation Reaction for Direct
Nitroquinoline Synthesis. Inorg. Chem. 2017, 56, 5953ꢀ5958. (e)
Nageswar Rao, D.; Rasheed, S.; Raina, G.; Ahmed, Q. N.;
Jaladanki, C. K.; Bharatam, P. V.; Das, P. CobaltꢀCatalyzed
Regioselective Ortho C(sp2)ꢀH Bond Nitration of Aromatics
through ProtonꢀCoupled Electron Transfer Assistance. J. Org.
Chem. 2017, 82, 7234ꢀ7244.
(13) John, A.; Nicholas, K. M. Palladium Catalyzed C–H
Functionalization
of OꢀArylcarbamates:
Selective orthoꢀ
Bromination Using NBS. J. Org. Chem. 2012, 77, 5600ꢀ5605.
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