Regiospecific synthesis of nitroarenes by palladium-catalyzed nitrogen-donor-directed aromatic C-H nitration

Article abstract of DOI:10.1002/chem.201002581

Nitration of N-heteroaromatics: The first example of palladium-catalyzed direct ortho-nitration of aryl C-H bonds is described. A range of azaarenes, such as 2-arylquinoxalines, pyridines, pyrazoles, and O-methyl oximes, were nitrated with excellent chemo- and regioselectivity (see scheme; DCE=1,2-dichloroethane). Preliminary mechanistic investigations support a silver-mediated radical mechanism involving palladium(II/III) and/or palladium(II/IV) catalytic cycles under oxidizing conditions. Copyright

Full text of DOI:10.1002/chem.201002581

DOI: 10.1002/chem.201002581
Regiospecific Synthesis of Nitroarenes by Palladium-Catalyzed Nitrogen-
À
Donor-Directed Aromatic C H Nitration
Yun-Kui Liu,* Shao-Jie Lou, Dan-Qian Xu, and Zhen-Yuan Xu*[a]
Aromatic nitro compounds are fundamental raw materials
in the production of dyes, plastics, perfumes, explosives, and
pharmaceuticals.[1] The nitrating agent-mediated electrophil-
ic aromatic substitution has long been the classical synthetic
approach for the preparation of nitroarenes.[2] However,
there are several persistent problems, such as unsatisfactory
regioselectivity, as well as imperfect functional group and/or
substrate (especially for heteroaromatics) compatibility, that
are always associated with the nitration processes. Besides,
the site at which a nitro group is introduced largely depends
on the orientation effect of different functional groups. To
overcome these central challenges, several strategic ap-
proaches have recently been developed including an ipso-ni-
protocol involving the ipso-oxidation of an amino or azide
group to a nitro group (Scheme 1c).[8,9] Although these strat-
egies can completely or partially overcome the abovemen-
tioned problems and serve as promising approaches for the
synthesis of nitroarenes, they all suffer from the use of pre-
functionalized starting materials. In view of the encouraging
À
achievements made in recently popularized C H activation
reactions,[10] we envisioned that transition metal-catalyzed
À
direct cross-coupling between an Ar H and a nitrite anion
in a site-selective manner would be an ideal alternative ap-
proach to access nitroarenes (Scheme 1d).[11] Herein, we
report on the first example of a palladium-catalyzed direct
À
ortho-nitration of aryl C H bonds in a series of azaarenes
tration protocol[3] by the nitrodemetalation of an aryl C M
using a nitrogen donor as the directing functional group.[12,13]
Our study commenced with the direct ortho-nitration of a
quinoxaline-tethered aromatic ring mainly due to the poten-
tial uses of quinoxaline derivatives[14] in materials science,
chemical, and pharmaceutical fields.[15] When model sub-
strate 1a was subjected to cross-coupling conditions with
À
bond (M=B, Li) (Scheme 1a)[4,5] or by transition-metal cata-
lyzed (Cu or Pd) transformation of aryl halides, triflates, and
nonaflates to nitroarenes developed by Saito[6] and Buch-
wald,[7] respectively (Scheme 1b), and an indirect nitration
NaNO2 in 1,2-dichloroethane (DCE) catalyzed by PdACHTUNGTRENNUNG(OAc)2
(10 mol%) with K2S2O8 (2.0 equiv) as an oxidant, the ortho-
nitration product 2a was indeed isolated in 28% yield
(Table 1, entry 1). However, it seemed that the reaction was
sensitive to several factors including the palladium and ni-
trite sources, oxidants, and solvents. Through systematically
screening these parameters,[16] we were finally able to estab-
lish optimized reaction conditions under which 1a cross-cou-
pled with AgNO2 to give the target product 2a in 86% yield
(Table 1, entry 4).
Scheme 1. Strategies for the regioselective synthesis of nitroarenes.
With optimized reaction conditions in hand, the scope of
the Pd-catalyzed ortho-nitration of quinoxaline derivatives 1
with AgNO2 was investigated (Table 2).[16] It was found that
electron-rich aryl rings generally afforded the target prod-
ucts in moderate to high yields (76–93%; Table 2, entries 1–
7). The present procedure also enabled the ortho-nitration
of electron-deficient aryl rings, albeit with lower yields (35–
51%; Table 2, entries 8–10, 12). A heterocyclic ring, namely
thiophene, was ortho-nitrated in 35% yield (Table 2,
entry 14). However, a furyl ring failed to be nitrated
(Table 2, entry 15). Notably, a series of functional groups, in-
[a] Prof. Dr. Y.-K. Liu, Dr. S.-J. Lou, Prof. Dr. D.-Q. Xu, Z.-Y. Xu
State Key Laboratory Breeding Base
of Green Chemistry-Synthesis Technology
Zhejiang University of Technology
Hangzhou, 310014 (China)
Fax : (+86)571-8832-0066
E-mail: ykuiliu@zjut.edu.cn
greensyn@zjut.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002581.
13590
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Chem. Eur. J. 2010, 16, 13590 – 13593

COMMUNICATION
[a]
À
À
Table 1. Selected conditions for aryl C H bond nitration.
Table 2. Pd-catalyzed ortho-nitration of aromatic C H bonds directed by
a quinoxaline ligand.[a]
Entry
[Pd]
MNO2/[O]
Yield [%][b]
1
2
3
4
5
6
7
8
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
N
NaNO2/K2S2O8
KNO2[c]/K2S2O8
ACHTUGNERTN(NUNG TBA)NO2/K2S2O8
AgNO2/K2S2O8
AgNO2/Oxone
AgNO2/CAN
AgNO2/BQ
28
trace
trace
Entry Substrate 1
Product 2
Yield [%][b]
86(45[d]
82
)
73
trace
1a–1m
2a–2m
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
AgNO2/PhI
N
<5
12
39
<5
56
0
1
1a: R=H
86
76
88
93
82
81[c]
87
35
44
50
0
9
AgNO2/Cu(OAc)2
ACHTUNGTRENNUNG
2
3
4
5
6
7
8
1b: R=4-Me
1c: R=4-OMe
1d: R=2-OMe
1e: R=3-OMe
1 f: R=4-OH
1g: R=4-Ph
1h: R=4-F
10
11
12
13
PdCl2
Pd
(OAc)2/2,2’-bipyridyl[e]
[PdCl2A(PPh3)2]
AgNO2/K2S2O8
AgNO2/K2S2O8
AgNO2/K2S2O8
AgNO2/K2S2O8
G
CHTUNGTRENNUNG
–
[a] Reaction conditions: compound 1a (0.3 mmol), [Pd] (0.03 mmol),
MNO2 (0.6 mmol), [O] (0.6 mmol) in DCE (3.5mL) at 1308C for 48 h.
[b] Yield of the isolated product. [c] [18]Crown-6 (0.6 mmol) was added
as a phase-transfer catalyst (PTC). [d] AgNO2 (0.3 mmol) and K2S2O8
(0.3 mmol) were used. [e] 0.036 mmol of 2,2’-bipyridyl. TBA=tetrabutyl-
ammonium, CAN=ceric ammonium nitrate, BQ=p-benzoquinone.
9
1i: R=4-Cl
10
11
12
13
1j: R=4-Br
1k: R=4-CN
1l: R=2-OAc
1m: R=3,4-OCH2O
51
0
2m
cluding methoxy (Table 2, entries 3–5), hydroxyl (entry 6),
halo (F, Cl, Br, entries 8–10), and acetoxy (entry 12) were
well tolerated under the reaction conditions, which would
provide opportunities for further functionalization. Double-
14
15
35
0
1n
1o
2n
2o
À
centered C H nitration directed by each nitrogen donor in
the quinoxaline moiety was also feasible (Table 2, entries 17
and 18).
Next, exploration of the present nitrating protocol for
other N-donor tethered aromatics (e.g., 2-arylpyridines, ben-
zo[h]quinoline, and 2-arylpyrazoles) was carried out
(Table 3), and the desired nitroarenes were obtained in 32–
61% yields (Table 3, entries 1–9).[16] Among all surveyed
donors at the present stage, quinoxaline represented the
16
17
46
1p
1q
1r
2p
2q
2r
60[d]
À
most effective directing group for the C H nitration. In all
cases, the reaction gave mononitration products predomi-
nantly (>95%). The ortho-regiochemistry of the nitrating
reaction was unambiguously established on the basis of the
spectral analyses, which was further confirmed by X-ray dif-
fraction analysis of a related derivative 2c (Figure 1).
To test whether the present strategy could be applied in
the regioselective nitration of removable N-donor tethered
aromatics, acetophenone O-methyl oximes were prepared.
Gratifyingly, 2-nitrated acetophenones were conveniently
prepared from the corresponding acetophenones in a three-
step process (Scheme 2), which is difficult using traditional
nitrating processes.
18
55[d]
[a] Reaction conditions: Compound 1 (0.3 mmol), PdACTHNUGTRENUNG(OAc)2 (0.03 mmol),
AgNO2 (0.6 mmol), K2S2O8 (0.6 mmol) in DCE (3.5 mL) at 1308C for
48 h. [b] Yield of the isolated product. [c] AgNO2 (0.3 mmol) and K2S2O8
(0.3 mmol) were used. [d] AgNO2 (0.9 mmol), K2S2O8 (0.9 mmol), and
PdACTHNUTRGENUG(N OAc)2 (0.045 mmol) were used.
Finally, preliminary experiments were performed to gain a
[16]
À
mechanistic insight into the C H nitration.
A binuclear
palladacycle 9 originating from 3a also catalyzed the nitra-
tion reaction (4a: 67% yield as determined by GC).[17] The
reaction exhibited a primary kinetic isotope effect both in
the intramolecular (kH/kD =5.3) and intermolecular (kH/kD =
4.6) competition experiments, consistent with a rate-deter-
mining cyclopalladation step. When the reaction was per-
formed under the standard conditions in the presence of
Chem. Eur. J. 2010, 16, 13590 – 13593
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13591

Y.-K. Liu, Z.-Y. Xu et al.
À
Table 3. Pd-catalyzed ortho-nitration of the aromatic C H bond in 3 di-
rected by other nitrogen donors.[a]
Entry
Substrate 1
Product 2
Yield [%][b]
Scheme 2. Synthesis of 2-nitrated acetophenones from acetophenones.
Reaction conditions: i) Compound
(1.2 equiv), pyridine (15 mL), methanol (100 mL), reflux, overnight. ii)
Compound 6 (0.3 mmol), Pd(OAc)2 (0.03 mmol), AgNO2 (0.6 mmol),
5
(0.04 mol), MeONH2·HCl
AHCTUNGTRENNUNG
K2S2O8 (0.6 mmol) in DCE (3.5 mL) at 1308C for 48 h. iii) Compound 7
(1.0 mmol), 12m HCl (4 mL), Et2O (4 mL), RT for 24 h.
3a–3 f
3a: R=H
4a–4 f
4a
4b
4c
4d
1
2
3
4
5
6
42
32
56
52
38
57
3b: R=2-Me
3c: R=4-F
3d: R=4-Cl
3e: R=3-Cl
3 f: R=4-Br
4e
4 f
4g
7
45 (1:1)[c]
3g
4g’
8
9
61[d]
3h
3i
4h
4i
55[d]
Scheme 3. Proposed mechanism.
[a] Reaction conditions: Compound 3 (0.3 mmol), PdACTHNUGTRENUNG(OAc)2 (0.03 mmol),
AgNO2 (0.6 mmol), K2S2O8 (0.6 mmol) in DCE (3.5 mL) at 1308C for
48 h. [b] Yield of the isolated product. [c] Determined on the basis of
1H NMR spectroscopic analysis. [d] CAN (0.6 mmol) was used as the oxi-
dant.
ACTHNUTRGNEUNG
III)[13b–c] and/or palladium(II/IV)[13a,21] catalytic cycles under
oxidizing conditions (Scheme 3).[13d–e]
In summary, we have described a highly regioselective ap-
proach to nitroarenes involving palladium-catalyzed direct
À
ortho-nitration of aromatic C H bonds guided by a nitrogen
functional group. This new approach to nitroarenes has char-
acteristic advantages: 1) the direct use of azaarenes as sub-
strates, without the need for prefunctionalization; 2) high
mononitration selectivity and regiospecific nitration in the
ortho-position relative to the nitrogen donors, independent
of the effect of other functionalities; 3) broad functional
group tolerance and, in particular, compatibility with N-het-
eroaromatics under neutral conditions. Further studies will
focus on the investigation of the mechanism, as well as the
exploration of this approach for the development of new
Figure 1. X-ray crystal structure of nitroarene 2c. Ellipsoids at 50% prob-
ability.
À
ligand-directed and/or new metal-catalyzed C H nitrations.
Experimental Section
TEMPO (2.0 equiv), a radical scavenger,[18] the reaction
failed to give any nitrated products, supporting a silver-
À
Typical procedure for the palladium-catalyzed C H nitration: Compound
mediated radical mechanism[11a,19,20] involving palladium
(II/
1a (61.8 mg, 0.3 mmol), Pd
U
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Regiospecific Synthesis of Nitroarenes
COMMUNICATION
0.6 mmol), K2S2O8 (162.0 mg, 0.6 mmol), and anhydrous DCE (3.5 mL)
were sequentially added to a 10 mL tube. Then the tube was sealed and
stirred at 1308C for 48 h. Upon completion, the resulting mixture was di-
luted with CH2Cl2 (10 mL) and filtered through Celite. After evaporation
of the solvent under vacuum, the residue was purified by column chroma-
tography on silica gel (100–200 mesh) with petroleum ether/EtOAc (4:1,
v/v) as eluent to give the desired product 2a 64.8 mg (86%) as a pale
yellow solid.
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[11] For examples of stoichiometric amounts of redox metal complexes
À
in the direct cross-coupling of Ar H and nitrite anions, see: a) B.
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CCDC-781968 contains the supplementary crystallographic data for 2c.
These data can be obtained free of charge from The Cambridge Crystal-
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À
[12] For reviews on C H aminations, see: a) H. M. L. Davies, J. R. Man-
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À
[13] For selected examples of nitrogen-donor-directed C H functionali-
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Acknowledgements
We gratefully thank the Natural Science Foundation of Zhejiang Prov-
ince (grant no.: Y4100201), the Foundation of Education of Zhejiang
Province (grant no.: Z200803599), Science and Technology Department
of Zhejiang Province and the Opening Foundation of Zhejiang Provincial
Top Key Discipline for financial support.
À
[14] For examples of quinoxaline as an N donor for C H activations,
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M. Zçllner, C. Daniliuc, P. G. Jones, W. Kowalsky, H.-H. Johannes,
Inorg. Chem. 2010, 49, 397; also see reference [13f].
À
Keywords: C H activation · heterocycles · nitroarenes ·
palladium · regioselectivity
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Received: September 6, 2010
Published online: November 9, 2010
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