KMnO4-mediated direct C2-selective C?H arylation of quinoline N-oxides with aromatic hydrazines

Article abstract of DOI:10.1016/j.tet.2016.11.070

An efficient protocol for the synthesis of 2-arylquinoline N-oxides has been developed via KMnO₄-mediated cross-coupling reaction of quinoline N-oxides with aromatic hydrazines in moderated to good yields. The reactions proceeded efficiently over a broad range of substrates with excellent regioselectivity and functional group tolerance.

Full text of DOI:10.1016/j.tet.2016.11.070

Accepted Manuscript
KMnO -mediated direct C2-selective C−H arylation of quinoline N-oxides with
4
aromatic hydrazines
Jin-Wei Yuan, Wei-Jie Li, Yong-Mei Xiao
PII:
S0040-4020(16)31250-9
10.1016/j.tet.2016.11.070
TET 28284
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 19 October 2016
Revised Date: 24 November 2016
Accepted Date: 28 November 2016
Please cite this article as: Yuan J-W, Li W-J, Xiao Y-M, KMnO -mediated direct C2-selective C
4
−H arylation of quinoline N-oxides with aromatic hydrazines, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.11.070.
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ACCEPTED MANUSCRIPT
Graphic Abstract
KMnO4-mediated direct C2-selective C-H arylation of quinoline
N-oxides with aromatic hydrazines
Jin-Wei Yuan,* Wei-Jie Li, Yong-Mei Xiao*
School of Chemistry & Chemical Engineering, Henan University of Technology; Academician
Workstation for Natural Medicinal Chemistry of Henan Province, Zhengzhou 450001, PR China
An efficient protocol for the synthesis of 2-arylquinoline N-oxides has been developed via
KMnO4-mediated cross-coupling reaction of quinoline N-oxides with arylhydrazines in mild
conditions with moderated to good yields.

ACCEPTED MANUSCRIPT
KMnO4-mediated direct C2-selective C−H arylation of quinoline
N-oxides with aromatic hydrazines
Jin-Wei Yuan,* Wei-Jie Li, Yong-Mei Xiao*
School of Chemistry & Chemical Engineering, Henan University of Technology; Academician
Workstation for Natural Medicinal Chemistry of Henan Province, Zhengzhou 450001, PR China
Abstract: An efficient protocol for the synthesis of 2-arylquinoline N-oxides has been developed
via KMnO4-mediated cross-coupling reaction of quinoline N-oxides with aromatic hydrazines in
moderated to good yields. The reactions proceeded efficiently over a broad range of substrates
with excellent regioselectivity and functional group tolerance.
Key words: 2-arylquinoline N-oxide; arylhydrazine; KMnO4-mediated; arylation; radical reaction
1. Introduction
The quinoline scaffold is one of the most important heterocycles and is commonly encountered
in natural products, medicinal and material chemistry.[1] In medicinal chemistry, quinolines and
quinoline N-oxides exhibit antitumor and antimalarial activities.[2] In addition, the quinoline
N-oxide core has been found in drugs that activate microsomal Na/K-ATPase.[3] As a result,
considerable efforts have been made towards their synthesis and functionalization in different
positions.[4] 2-Arylquinoline N-oxide derivatives are important structural motifs with applications
in the areas of drug discovery,[5] and their synthesis by novel methods has attracted attention in
medicinal and synthetic chemistry.
Transition-metal catalyzed direct arylations of quinoline N-oxide through C−H bond cleavages
have recently been reported,[6] and widely employed among these reactions is the Pd-catalyzed
cross-coupling of aromatic halides, and boronic acids, etc. In 2015, Larionov’s group reported a
palladium-catalyzed C8-selective C−H arylation of quinoline N-oxides using iodoarene as a
coupling partner, and the main product 8-arylquinoline N-oxides were produced (Scheme 1 a).[7]
In 2009, a Pd(OAc)2-catalyzed direct arylation reaction was described by Fagnou’s group using the
substrates of quinoline N-oxides with bromoarenes, PtBu3-HBF4 for the ligand, K2CO3 for the base
in toluene; In 2011, Ackermam’s group reported a direct arylation of electron-deficient quinoline
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N-oxides with aryl tosylates using Pd(OAc)2 as a catalyst derived from the ligand X-Phos, CsF as
the base in a t-BuOH/toluene solvent mixture; In 2014, decarboxylative cross-coupling reactions
of substituted 2-carboxyazine N-oxides, with a variety of (hetero)aryl halides, by bimetallic
Pd0/CuI and Pd0/AgI catalysis were reported by Hoarau’s group, and Pd(OAc)2-catalyzed direct
arylation of azine and quinoline N-oxides using aryl triflates to afford the corresponding 2-aryl
azine and quinoline N-oxides was also described by Fagnou’s group (Scheme 1 b).[8]
Transition-metal-free reactions are of great interest in terms of atom economy, environmental
impact, and cost reduction. In 2015, a metal-free regioselective cross-coupling of quinoline
N-oxides with boronic acids was developed by Antonchick’s group in DMSO solvent at 110 oC for
1-24 h, and Morris’ group also reported the synthesis of 7-aryl-1,8-naphthyridines via addition of
o
aryl boronic acids to 1,8-naphthyridine N-oxides at 110 C in toluene or dimethylformamide for
16 h (Scheme 1 c).[9] Moreover, Organocatalytic functionalization of quinoline N-oxide was also
investigated using in situ generated onium amide base or phophazene base as a catalyst,
heteroarylation at 2-position were achieved via nucleophilic addition- elimination process.[10]
Transition-metal or metal-free catalyzed cross coupling reactions of quinoline N-oxides with
different aryl sources represent some of the most important methods for synthesizing
2-arylquinoline N-oxides. However, the common limitations of most of these methods are
inevitability of transition-metals which possess high cost and toxicity, necessity of
prefunctionalization of 2-position of quinoline N-oxides, use of expensive arylating counterparts
o
such as boronic acid, elevated temperature (110-150 C), and longer reaction time (12-16 h).
Recently, although there were reports on constructing 2-arylquinoline N-oxides through the
reduction-cyclization sequences starting from 2-nitrochalcones and 3-hydroxyketones using
ruthenium-carbon nanotube nanohybridas a catalyst,[11] the applicability of such methods is
curtailed owing to the requirement of drastic conditions such as reflux temperatures, excess
amounts of metal catalysts, or unavailable and expensive catalysts.
Previous works:
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This work:
Scheme 1 Synthesis of 2-arylquinolines and 2-arylquinoline N-oxides
Although direct arylation reaction of quinoline N-oxides has been investigated thoroughly with
many coupling partners, there are no reports employing the use of arylhydrazines. Arylhydrazines
are known to undergo oxidation to form aryl radicals in the presence of oxygen, high valent metal
or other oxidants.[12] Furthermore, arylhydrazines are simple and cheap starting materials. We
previously reported the direct and regioselective arylation of coumarins and quinolinones using a
wide range of arylhydrazines to produce 3-arylcoumarin and 3-arylquinolinone derivatives under
mild conditions.[13] Guided by the recent studies on using arylhydrazines as aryl sources,[14] we
decided to investigate the modular synthesis for 2-arylquinoline N-oxides by this method. Herein,
we report such transformations starting from quinoline N-oxides with arylhydrazines that lead to
2-arylquinoline N-oxide derivatives in high yields (Scheme 1 d). The attractive features of this
o
method are the use of simple KMnO4 as an oxidant at moderate reaction temperature (90 C); a
broad evaluation of the scope and functional group compatibilities for quinoline N-oxides and
arylhydrazines; the highly regioselective arylation of substituted quinoline N-oxides. In addition,
no catalyst, ligand, base, and other additive are needed.
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2. Results and discussion
Table 1 Optimization of reaction conditionsa
NHNH2
Oxidant
+
N
O
N
O
H
Solvent, Temp.
1a
2a
3a
Time (mins) Yieldb (%)
Entry
1
Oxidant (eq)
H2O2 (3.0)
TBHP (3.0)
DTBP (3.0)
Solvent
Temp (oC)
CH3CN
CH3CN
CH3CN
80
80
80
80
80
80
80
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
10
20
40
80
60
51
53
20
5
2
3
4
Mn(OAc)3 (3.0) CH3CN
5
MnO2 (3.0)
KMnO4 (3.0)
KMnO4 (2.0)
KMnO4 (2.0)
KMnO4 (2.0)
KMnO4 (2.0)
KMnO4 (2.0)
KMnO4 (2.0)
KMnO4 (2.0)
KMnO4 (2.0)
KMnO4 (2.0)
KMnO4 (2.0)
KMnO4 (2.0)
KMnO4 (2.0)
KMnO4 (2.0)
KMnO4 (2.0)
/
CH3CN
CH3CN
H2O
60
65
5
6
7
8
1,4-dioxane
CH3OH
DMSO
DCE
80
80
80
80
80
60
70
90
100
90
90
90
90
90
35
20
<5
60
42
62
70
85
80
25
40
65
79
0
9
10
11
12
13
14
15
16
17
18c
19
20
21
THF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
a
Reaction conditions: quinoline N-oxide 1a (0.3 mmol, 43.5 mg), phenylhydrazine 2a (0.6 mmol, 64.8 mg),
oxidant and solvent (3.0 mL).
b Isolated yield.
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The reaction between quinoline N-oxide (1a) and phenylhydrazine (2a) was examined as a model
reaction to optimize the reaction condition (Table 1). Initially, different oxidants were used when
o
the reaction was carried out in CH3CN at 80 C for 60 mins. The result showed that oxidants
tert-butyl peroxide (DTBP) and Mn(OAc)3 gave the desired product (3a) in low yields (Table 1,
entry 3 and 4), and oxidants H2O2, tert-butyl hydroperoxide (TBHP), MnO2, and KMnO4 produced
3a with moderated yields (Table 1, entries 1, 2, 5, and 6). KMnO4 proved to be the most effective
oxidant to give 3a in 65% yield (Table 1, entry 6). The amount of KMnO4 was also investigated
(Supporting information, Table S1, entries 1-5). The best yield was 70% when 2.0 eq KMnO4 was
used. Subsequently, The ratio of substrates quinoline N-oxide and phenylhydrazine was examined,
and the ratio 1:1.5 of quinoline N-oxide and phenylhydrazine proved to be the best result,
providing 75% yield of 3a (Supporting information, Table S2, entries 1-5). Different solvents
including CH3CN
, H2O, 1,4-dioxane, CH3OH, DMSO, DCE, and THF were screened (Table S2, entry 3,
and Table 1, entries 7-12), CH3CN was found to be best solvent for this transformation. With the
o
o
reaction temperature improving from 60 C to 90 C, the product yields dramatically enhanced.
However, the yield dropped slightly when the reaction temperature was increased more than 90
oC, and the optimal reaction temperature was 90 oC (Table 1, entries 13-16). Finally, the reaction
time was also examined, and 60 mins could obtain good yield (Table 1, entries 15, 17-20). In the
absence of the oxidant KMnO4, the desired product was not obtained (Table 1, entry 21).
With the optimized conditions in hand, the scope of this cross-coupling was undertaken by
investigating the reaction between quinoline N-oxides (1) and arylhydrazine (2) (Scheme 2). The
reaction of arylhydrazines bearing electron-donating and electron-withdrawing groups with
quinoline N-oxides processed smoothly and afforded the corresponding products 3a-3p in
moderate to good yields. Moreover, arylhydrazines bearing electron-donating groups could give
better yields (84-95%) than those with electron-withdrawing groups (53-68%). We were pleased
to observe the formation of the desired C2-arylated products, 3h, 3i and 3m, in reasonable to
moderated yields (57-63%). Remarkably, the electronic and steric hindrance effects of coupling
partner arylhydrazines have no influence on the success of the coupling reaction. It was
noteworthy that arylhydrazine halides were well tolerated, providing handles for further
functionalization. Remarkably, all reactions featured a high regioselectivity in that the C2 arylated
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Table 2 Synthesis of 2-arylquinoline N-oxides from quinoline N-oxides and arylhydrazines a,b
N
O
N
O
N
O
3a (85%)
3b (86%)
3c (87%)
N
O
N
O
N
O
O
3d (90%)
3e (87%)
3f (95%)
F
Br
Cl
N
O
N
O
N
O
3g (84%)
3h (63%)
3i (65%)
F
N
O
N
O
N
O
Br
F
3j (69%)
3k (68%)
3l (70%)
F
N
O
N
O
N
O
CF3
F
OCF3
3m (57%)
3n (55%)
3o (53%)
Br
N
O
N
O
N
O
CN
O
O
3p (58%)
3q (85%)
3r (90%)
Br
O
O2N
N
O
N
N
O
O
O
3s (75%)
3t (87%)
3u (0%)
N
N
O
O
N
O
3v (82%)
3w (62%)
3x (70%)
a
Reaction conditions: quinoline N-oxide 1 (0.3 mmol), arylhydrazine 2 (0.45 mmol), KMnO4 (0.6 mmol, 94.8 mg)
in 3.0 mL CH3CN solvent, 90 oC for 60 min.
b Isolated yield.
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Figure 1 X-ray crystal structure of 3n
products 3 were exclusively formed. The crystallization of product 3n from CHCl3 gave a single
crystal suitable for X-ray analysis. It illustrates the molecular structure of the substituted
2-arylquinoline N-oxide 3n (Figure 1).
The scope of this methodology was also investigated with respect to quinoline N-oxides (Table 2,
3q-3u). Quinoline N-oxides bearing electron-donating groups (-CH3, -OCH3) and
electron-withdrawing group (-Br) could react smoothly with arylhydrazines to afford the
corresponding products. However, quinoline N-oxides possessing a strong electron-withdrawing
-NO2 group at the C6 position didn’t give the desired product 3u. Pleasingly, the coupling reaction
of 3-bromoquinoline N-oxides with 3-methoxyl phenhydrazine could proceed to afford the
product 3q in 85%, which indicated that the steric effect played a weak role in this transformation.
Gratifying, aliphatic hydrazine, t-butyl hydrazine could also react with quinoline N-oxide to obtain
2-t-butyl quinoline N-oxide 3v. To further examine the versatility of this methodology,
isoquinoline N-oxide was employed as a coupling partner. Fortunately, the desired products (3w
and 3x) could be produced under the standard condition. Remarkably, the transformations were
regioselective, and the ratio of C1-arylated and C3-arylated isoquinoline N-oxides were about 5:1.
Pd(OAc)2, dppf
N
O
N
Et3N, CH3CN
110oC, 1.0 h
O
O
3f
3f'
(Yield: 60%)
Scheme 2 The deoxygenation of 2-(4-methoxyphenyl)quinoline N-oxide
To further demonstrate the utility of this method, the reduction of 2-arylquinoline N-oxides to
the parent 2-arylquinolines were also investigated. There has been a considerable amount of
research devoted to developing improved procedures for deoxygenation.[15] Herein, we further
examined the reduction reaction of 2-arylquinoline N-oxide (3f) using Pd(OAc)2 as a catalyst and
1,1′-bis(diphosphino)ferrocene (dppf) as ligand, triethylamine used as the base in CH3CN at 120
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oC for 1.0 h under microwave irradiation.[16] The reaction proceeded smoothly and the
deoxidized product 3f′ was obtained with 60% yield.
Scheme 3 Proposed reaction mechanism
On the basis of the previous studies[12], a plausible reaction mechanism for this coupling
reaction described above is proposed in Scheme 3. The phenylhydrazine A is firstly oxidized by
KMnO4 to form a phenyldiazene B. The diazene B is then rapidly converted a phenyl radical C by
the release of N2 in the presence of KMnO4. The N-oxide moiety increases the electron-density of
the electron-deficient pyridine ring system. The phenyl radical C can selectively add to C2 position
of quinoline N-oxide to produce a radical intermediate D, allowing the carbocation intermediate E
to be formed by a single-electron transfer. Finally, the intermediate E lose a proton to make the
C2 arylated quinoline N-oxide F.
Figure 2 Gibbs energies for different radicals investigated by DFT calculations
Scheme 4 A controlled experiment
The high regioselectivity of the arylation process at C2 versus C3 and C4 was further explored
with the assistance of DFT calculations. The regioselectivity was explained by examining the
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stability of the radical intermediate. When phenyl radical attacks on C2, C3 and C4 of quinoline
N-oxide, the radicals D, D’, and D’’ were obtained, respectively. The DFT calculation results
showed that the Gibbs energies of the radicals D, D’, and D’’ were 11.77 kcal/mol, 17.07 kcal/mol,
and 13.13 kcal/mol, respectively (Figure 2). The radical D presents much lower Gibbs energy for
the C2 than the C3 and C4 products. A controlled experiment was investigated. When 2-methyl
quinoline N-oxide was employed as a substrate to react with phenylhydrazine, the reaction could
not proceed and no product was obtained (Scheme 4). Therefore, both DFT calculation and
experimental result go in the same direction and indicate a preferred C2 attack.
3. Conclusion
In conclusion, we have disclosed a direct C2-selective C-H arylation of quinoline N-oxides with
arylhydrazines under mild conditions. The methodology features inexpensive reagents, a broad
range of substrates, excellent regioselectivity and functional group tolerance, as well as
experimental simplicity.
4. Experimental
4.1 General information
All substrates purchased from J & K Scientific Ltd. were used without further purification. Column
chromatography was performed using 300-400 mesh silica with the indicated solvent system
according to standard techniques. Nuclear magnetic resonance spectra were recorded on Bruker
1
Avance 400 MHz spectrometer. Chemical shifts for H NMR spectra are recorded in parts per
million from tetramethylsilane. Data were reported as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, m = multiplet and br = broad), coupling constant in Hz and
integration. Chemical shifts for 13C NMR spectra were recorded in parts per million from
tetramethylsilane. High resolution mass spectra (HR MS) were obtained on Q-TOF instrument
using the ESI technique. IR spectra were recorded on Shimadazu IR-408 Fourier transform
infrared spectrophotometer using a thin film supported on KBr pellets. Melting points were
measured on an XT4A microscopic apparatus uncorrected.
4.2 General experimental procedure for the synthesis of 2-arylquinoline N-oxides (3)
Quinoline N-oxides
1 (0.3 mmol), arylhydrazines 2 (0.45 mmol), and KMnO4 (0.6mmol,
94.8 mg) in acetonitrile (3.0 mL) were added to a 25 mL Schlenk tube. The mixture was
o
heated at 90 C for 60 mins (monitored by TLC). After completion of the reaction, the
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solvent was distilled under vacuum. 10 mL ethylacetate was added to the residuum, and
30 mL saturated sodium chloride solution washed three times. The organic phase was
dried over anhydrous NaSO4 and concentrated under vacuum. The crude product was
purified by silica gel column chromatography to give the desired products
acetate/petroleum ether (1:10 to 1:3) as eluant.
3 using ethyl
4.2.1. 2-Phenylquinoline 1-oxide (3a)
o
o
Colorless solid, mp 145-146 C (EtOAc) [lit17 mp 148.5-149.7 C]. IR (KBr) ν(cm-1): 1462, 1377,
1352, 1302. 1H NMR (400 MHz, CDCl3) δ: 8.85 (d, JH-H = 8.7 Hz, 1H), 7.96 (d, JH-H = 7.3 Hz, 2H), 7.82
(d, JH-H = 8.1 Hz, 1H), 7.75 (t, JH-H = 7.7 Hz, 1H), 7.70 (d, JH-H = 8.7 Hz, 1H), 7.59 (t, JH-H = 7.4 Hz, 1H),
7.52-7.42 (m, 4H). 13C NMR (100 MHz, CDCl3) δ: 144.9, 142.2, 133.4, 130.5 (CH), 129.6 (CH), 129.5
(CH), 129.4, 128.4 (CH), 128.2 (CH), 128.0 (CH), 125.2 (CH), 123.3 (CH), 120.2 (CH). MS (ESI) m/z:
222.3 [M + H]+ (calcd for C15H12NO+ 222.1).
4.2.2. 2-(p-Tolyl)quinoline 1-oxide (3b)
o
o
Colorless solid, mp 125-126 C (EtOAc) [lit17 mp 127-128 C]. IR (KBr) ν(cm-1): 2954, 2918, 1502,
1
1456. H NMR (400 MHz, CDCl3) δ: 8.85 (d, JH-H = 5.3 Hz, 1H), 7.90 (d, JH-H = 7.6 Hz, 2H), 7.83 (d,
JH-H = 8.0 Hz, 1H), 7.76 (t, JH-H = 5.7 Hz, 1H), 7.70 (d, JH-H = 7.9 Hz, 1H), 7.61 (t, JH-H = 7.4 Hz, 1H),
7.50 (d, JH-H = 8.5 Hz, 1H), 7.32 (d, JH-H = 7.2 Hz, 2H), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3) δ:
145.2, 142.4, 139.7, 130.5 (CH), 130.4, 129.5 (CH), 129.4, 128.9 (CH), 128.2 (CH), 127.9 (CH),
125.2 (CH), 123.2 (CH), 120.2 (CH), 21.4 (CH3). MS (ESI) m/z: 236.3 [M + H]+ (calcd for C16H14NO+
236.1).
4.2.3. 2-(4-Ethylphenyl)quinoline 1-oxide (3c)
o
1
Light red solid, mp 108-109 C (EtOAc). IR (KBr) ν(cm-1): 3124, 3082, 1601, 1450. H NMR (400
MHz, CDCl3) δ: 8.86 (d, JH-H = 8.8 Hz, 1H), 7.92 (d, JH-H = 8.2 Hz, 2H), 7.85 (d, JH-H = 8.1 Hz, 1H), 7.78
(td, JH-H = 7.0 Hz, JH-H = 1.1 Hz, 1H), 7.73 (d, JH-H = 8.7 Hz, 1H), 7.63 (td, JH-H = 7.8 Hz, JH-H = 0.7 Hz,
1H), 7.51 (d, JH-H = 8.7 Hz, 1H), 7.35 (d, JH-H = 8.8 Hz, 2H), 2.73 (q, JH-H = 7.6 Hz, 2H), 1.29 (t, JH-H
=
7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 146.0, 145.1, 142.3, 130.7, 130.5 (CH), 129.6 (CH),
129.4, 128.2 (CH), 127.9 (CH), 127.8 (CH), 125.1 (CH), 123.3 (CH), 120.3 (CH), 28.8 (CH2), 15.4
(CH3). HR MS (ESI) m/z: 250.1224 [M + H]+ (calcd for C17H16NO+ 250.1226).
4.2.4. 2-(3,4-Dimethylphenyl)quinoline 1-oxide (3d)
Yellow solid, mp 144-145 oC (EtOAc). IR (KBr) ν(cm-1): 3122, 2918, 1558, 1496, 1400. 1H NMR (400
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MHz, CDCl3) δ: 8.85 (d, JH-H = 8.6 Hz, 1H), 7.81-7.80 (m, 2H), 7.76-7.64 (m, 3H), 7.59 (t, JH-H = 7.4
Hz, 1H), 7.47 (d, JH-H = 8.6 Hz, 1H), 7.26 (d, JH-H = 7.4 Hz, 1H), 2.33 (s, 3H), 2.31 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ: 145.3, 142.2, 138.4, 136.4, 130.9, 130.5 (CH), 130.4 (CH), 129.6 (CH), 129.4,
128.2 (CH), 127.9 (CH), 127.0 (CH), 125.3 (CH), 123.3 (CH), 120.2 (CH), 19.9 (CH3), 19.8 (CH3). HR
MS (ESI) m/z: 250.1228 [M + H]+ (calcd for C17H16NO+ 250.1226).
4.2.5. 2-(3,5-Dimethylphenyl)quinoline 1-oxide (3e)
o
o
Yellow solid, mp 91-92 C (EtOAc) [lit17 mp 94-95 C]. IR (KBr) ν(cm-1): 3116, 3066, 1599, 1560,
1
1400. H NMR (400 MHz, CDCl3) δ: 8.85 (d, JH-H = 8.8 Hz, 1H), 8.02 (d, JH-H = 8.8 Hz, 2H), 7.82 (d,
JH-H = 8.0 Hz, 1H), 7.75 (td, JH-H = 7.1 Hz, JH-H = 1.0 Hz, 1H), 7.70 (d, JH-H = 8.7 Hz, 1H), 7.60 (td, JH-H =
7.8 Hz, JH-H = 0.7 Hz, 1H), 7.55 (bs, 2H), 7.45 (d, JH-H = 8.7 Hz, 1H), 7.09 (s, 1H), 2.39 (s, 6H). 13C
NMR (100 MHz, CDCl3) δ: 145.4, 142.2, 137.8, 133.4, 131.2 (CH), 130.4 (CH), 129.5, 128.3 (CH),
127.9 (CH), 127.2 (CH), 125.1 (CH), 123.4 (CH), 120.2 (CH), 21.4 (CH3). MS (ESI) m/z: 250.3 [M +
H]+ (calcd for C17H16NO+ 250.1).
4.2.6. 2-(4-Methoxyphenyl)quinoline 1-oxide (3f)
o
Yellow solid, mp 105-106 oC (EtOAc) [lit17 mp 124.9-126.0 C]. IR (KBr) ν(cm-1): 3122, 2931, 1604,
1
1560, 1500, 1400. H NMR (400 MHz, CDCl3) δ: 8.84 (d, JH-H = 8.7 Hz, 1H), 8.02 (d, JH-H = 8.8 Hz,
2H), 7.82 (d, JH-H = 8.0 Hz, 1H), 7.75 (t, JH-H = 7.4 Hz, 1H), 7.70 (d, JH-H = 8.7 Hz, 1H), 7.59 (t, JH-H
=
7.7 Hz, 1H), 7.49 (d, JH-H = 8.7 Hz, 1H), 7.03 (d, JH-H = 8.8 Hz, 2H), 3.86 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ: 160.5, 144.6, 142.3, 131.2 (CH), 130.4 (CH), 129.2, 128.1 (CH), 127.9 (CH), 125.6, 125.2
(CH), 123.0 (CH), 120.1 (CH), 113.6 (CH), 55.3 (CH3). MS (ESI) m/z: 252.3 [M + H]+ (calcd for
C16H14NO2+ 252.1).
4.2.7. 2-(3-Chloro-4-methylphenyl)quinoline 1-oxide (3g)
Light yellow solid, mp 144-145 oC (EtOAc). IR (KBr) ν(cm-1): 3120, 2934, 1560, 1400. 1H NMR (400
MHz, CDCl3) δ: 8.82 (d, JH-H = 8.8 Hz, 1H), 8.03 (d, JH-H = 1.2 Hz, 1H), 7.84 (d, JH-H = 8.1 Hz, 1H),
7.79-7.71 (m, 3H), 7.62 (t, JH-H = 7.3 Hz, 1H), 7.46 (d, JH-H = 8.7 Hz, 1H), 7.35 (d, JH-H = 8.0 Hz, 1H),
2.43 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 143.6, 142.2, 137.7, 134.3, 132.4, 130.7 (CH), 130.6
(CH), 130.0 (CH), 129.5, 128.5 (CH), 128.0 (CH), 127.7 (CH), 125.3 (CH), 122.9 (CH), 120.2 (CH),
20.1 (CH3). HR MS (ESI) m/z: 270.0676 [M + H]+ (calcd for C16H13ClNO+ 270.0680).
4.2.8. 2-(2-Fluorophenyl)quinoline 1-oxide (3h)
o
1
Yellow solid, mp 140-141 C (EtOAc). IR (KBr) ν(cm-1): 1601, 1454. H NMR (400 MHz, CDCl3) δ:
8.85 (d, JH-H = 8.8 Hz, 1H), 7.87 (d, JH-H = 8.1 Hz, 1H), 7.78-7.62 (m, 4H), 7.48-7.42 (m, 2H),
11

ACCEPTED MANUSCRIPT
7.49-7.44 (m, 2H), 7.28 (t, JH-H = 7.1 Hz, 1H), 7.22 (t, JH-H = 8.8 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ: 161.4, 158.9, 142.1, 141.3, 131.4 (d, JF-C = 8.6 Hz, CH), 131.2 (d, JF-C = 2.8 Hz, CH), 130.5 (CH),
130.0, 128.4 (d, JF-C = 66.6 Hz, CH), 124.7 (CH), 124.1 (d, JF-C = 3.5 Hz, CH), 123.8 (d, JF-C = 1.7 Hz,
CH), 121.6 (d, JF-C = 14.1 Hz), 120.2 (CH), 116.0 (d, JF-C = 21.3 Hz, CH). 19F NMR (376 MHz, CDCl3) δ:
-111.0. HR MS (ESI) m/z: 240.0816 [M + H]+ (calcd for C15H11FNO+ 240.0819).
4.2.9. 2-(2-Bromophenyl)quinoline 1-oxide (3i)
o
1
Yellow solid, mp 164-165 C (EtOAc). IR (KBr) ν(cm-1): 1552, 1502, 1336, 808. H NMR (400 MHz,
CDCl3) δ: 8.83 (d, JH-H = 8.7 Hz, 1H), 7.91 (d, JH-H = 1.1 Hz, 1H), 7.81-7.72 (m, 3H), 7.68 (t, JH-H = 7.3
Hz, 1H), 7.49-7.44 (m, 2H), 7.38-7.33 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 145.2, 142.0, 135.3,
132.9 (CH), 131.0 (CH), 130.6 (CH), 130.5 (CH), 130.1, 128.7 (CH), 128.1 (CH), 127.5 (CH), 124.6
(CH), 123.5 (CH), 123.3, 120.3 (CH), 21.4 (CH3). HR MS (ESI) m/z: 300.0015 [M + H]+ (calcd for
C15H11BrNO+ 300.0019).
4.2.10. 2-(3-Fluorophenyl)quinoline 1-oxide (3j)
Light yellow solid, mp 143-144 oC (EtOAc). IR (KBr) ν(cm-1): 1589, 1452, 1342, 1255. 1H NMR (400
MHz, CDCl3) δ: 8.85 (d, JH-H = 8.8 Hz, 1H), 7.88 (d, JH-H = 8.1 Hz, 1H), 7.82-7.75 (m, 3H), 7.71 (d, JH-H
= 2.0 Hz, 1H), 7.66 (t, JH-H = 7.4 Hz, 1H), 7.51-7.46 (m, 2H), 7.18 (td, JH-H = 8.4 Hz, JH-H = 2.0 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ: 163.6, 161.2, 143.7, 142.3, 135.3 (d, JF-C = 8.3 Hz), 130.7 (CH), 129.8
(CH), 129.7 (d, JF-C = 22.8 Hz), 128.7 (CH), 128.0 (CH), 125.3 (d, JF-C = 3.3 Hz, CH), 123.0 (CH), 120.2
(CH), 116.8 (d, JF-C = 21.0 Hz, CH), 116.5 (d, JF-C = 18.7 Hz, CH). 19F NMR (376 MHz, CDCl3) δ: -112.6.
HR MS (ESI) m/z: 240.0823 [M + H]+ (calcd for C15H11FNO+ 240.0819).
4.2.11. 2-(4-Fluorophenyl)quinoline 1-oxide (3k)
Light yellow solid, mp 157-159 oC (EtOAc) [lit18 mp 162-164 oC]. IR (KBr) ν(cm-1): 1603, 1564, 1498,
1458, 1321, 1230, 814. 1H NMR (400 MHz, CDCl3) δ: 8.83 (d, JH-H = 8.8 Hz, 1H), 8.01 (dd, JH-H = 8.8
Hz, JF-H = 5.4 Hz, 2H), 7.85 (d, JH-H = 8.1 Hz, 1H), 7.80-7.73 (m, 2H), 7.65 (td, JH-H = 7.9 Hz, JH-H = 0.8
Hz, 1H), 7.47 (d, JH-H = 8.7 Hz, 1H), 7.21 (t, JH-H = 8.7 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ: 164.4,
161.9, 143.9, 142.2, 131.8 (d, JF-C = 8.3 Hz, CH), 130.6 (CH), 129.5, 129.4 (d, JF-C = 3.5 Hz), 128.5
(CH), 128.0 (CH), 125.3 (CH), 123.0 (CH), 120.1 (CH), 115.3 (d, JF-C = 21.4 Hz, CH). 19F NMR (376
MHz, CDCl3) δ: -111.0. MS (ESI) m/z: 240.3 [M + H]+ (calcd for C15H11FNO+ 240.0).
4.2.12. 2-(4-Bromophenyl)quinoline 1-oxide (3l)
Brown solid, mp 183-184 oC (EtOAc). IR (KBr) ν(cm-1): 1552, 1502, 1336, 808. 1H NMR (400 MHz,
12

ACCEPTED MANUSCRIPT
CDCl3) δ: 8.83 (d, JH-H = 8.6 Hz, 1H), 7.89-7.86 (m, 3H), 7.81-7.74 (m, 2H), 7.67-7.64 (m, 3H), 7.48
(d, JH-H = 8.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 143.9, 142.3, 132.2, 131.5 (CH), 131.2 (CH),
130.7 (CH), 129.6, 128.6 (CH), 128.0 (CH), 125.4 (CH), 123.9, 122.8 (CH), 120.2 (CH). HR MS (ESI)
m/z: 300.0023 [M + H]+ (calcd for C15H11BrNO+ 300.0019).
4.2.13. 2-(2,4-Difluorophenyl)quinoline 1-oxide (3m)
o
1
Colorless solid, mp 138-139 C (EtOAc). IR (KBr) ν(cm-1): 1605, 1564, 1450, 1456, 1230, 815. H
NMR (400 MHz, CDCl3) δ: 8.82 (d, JH-H = 8.8 Hz, 1H), 7.90 (d, JH-H = 8.0 Hz, 1H), 7.82-7.66 (m, 4H),
7.43 (d, JH-H = 8.6 Hz, 1H), 7.06-6.97 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 163.8 (dd, J = 255.6 Hz,
J = 10.5 Hz), 163.8 (d, J = 240.3 Hz), 160.6 (dd, J = 254.2 Hz, J = 11.5 Hz), 141.2 (d, J = 175.6 Hz),
132.4 (dd, J = 10.3 Hz, J = 4.5 Hz, CH), 130.7 (CH), 130.0, 128.8 (CH), 128.0 (CH), 124.9 (CH), 123.7
(d, J = 2.2 Hz, CH), 120.2 (CH), 117.8 (dd, J = 14.9 Hz, J = 5.0 Hz), 111.6 (dd, J = 20.9 Hz, J = 2.7 Hz,
CH), 104.6 (t, J = 25.8 Hz, CH). 19F NMR (376 MHz, CDCl3) δ: -106.8 (d, JF-F = 2.5 Hz), -107.0 (d, JF-F
2.5 Hz). HR MS (ESI) m/z: 258.0728 [M + H]+ (calcd for C15H10F2NO+ 258.0725).
4.2.14. 2-(4-(Trifluoromethyl)phenyl)quinoline 1-oxide (3n)
=
o
o
Colorless solid, mp 187-188 C (EtOAc) [lit19 mp 197-199 C]. IR (KBr) ν(cm-1): 1562, 1334, 1254,
1120, 816. 1H NMR (400 MHz, CDCl3) δ: 8.84 (d, JH-H = 8.8 Hz, 1H), 8.09 (d, JH-H = 8.2 Hz, 2H), 7.89
(d, JH-H = 8.1 Hz, 1H), 7.83-7.77 (m, 4H), 7.68 (t, JH-H = 7.4 Hz, 1H), 7.50 (d, JH-H = 8.7 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ: 143.6 (d, JF-C = 2.4 Hz), 142.2, 136.9, 131.3 (d, JF-C = 32.5 Hz), 130.9 (CH),
130.0 (CH), 129.8, 128.9 (CH), 128.1 (CH), 125.5 (CH), 125.3 (q, JF-C = 3.8 Hz), 122.8 (CH), 122.5,
120.2 (CH). 19F NMR (376 MHz, CDCl3) δ: -62.8. MS (ESI) m/z: 290.3 [M + H]+ (calcd for
C16H11F3NO+ 290.0).
4.2.15. 2-(4-(Trifluoromethoxy)phenyl)quinoline 1-oxide (3o)
Light yellow solid, mp 149-150 oC (EtOAc). IR (KBr) ν(cm-1): 1560, 1454. 1H NMR (400 MHz, CDCl3)
δ: 8.84 (d, JH-H = 8.8 Hz, 1H), 8.04 (d, JH-H = 8.8 Hz, 2H), 7.87 (d, JH-H = 8.1 Hz, 1H), 7.82-7.76 (m,
2H), 7.65 (t, JH-H = 7.3 Hz, 1H), 7.49 (d, JH-H = 8.7 Hz, 1H), 7.36 (d, JH-H = 8.8 Hz, 2H). 13C NMR (100
MHz, CDCl3) δ: 149.7 (d, JF-C = 1.7 Hz), 143.6, 142.2, 131.9, 131.3 (CH), 130.8 (CH), 129.6, 128.7
(CH), 128.0 (CH), 125.5 (CH), 122.9 (CH), 121.7, 120.6 (CH), 120.2 (CH). 19F NMR (376 MHz, CDCl3)
δ: -57.6. HR MS (ESI) m/z: 306.0739 [M + H]+ (calcd for C16H11F3NO2+ 306.0736).
4.2.16. 2-(4-cyanophenyl)quinoline 1-oxide (3p)
o
o
Colorless solid, mp 205-206 C (EtOAc) [lit19 mp 206-208 C]. IR (KBr) ν(cm-1): 2937, 2225, 1312,
13

ACCEPTED MANUSCRIPT
817. 1H NMR (400 MHz, CDCl3) δ: 8.79 (d, JH-H = 8.8 Hz, 1H), 8.08 (d, JH-H = 8.4 Hz, 2H), 7.88 (d, JH-H
= 8.1 Hz, 1H), 7.79-7.75 (m, 4H), 7.66 (t, JH-H = 7.2 Hz, 1H), 7.46 (d, JH-H = 8.7 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ: 142.9, 142.2, 137.8, 132.0 (CH), 131.0 (CH), 130.3 (CH), 129.1 (CH), 128.1 (CH),
125.6 (CH), 122.6 (CH), 120.1 (CH), 118.5, 112.9 (CH). MS (ESI) m/z: 247.2 [M + H]+ (calcd for
C16H11N2O+ 247.0).
4.2.17. 3-bromo-2-(4-methoxyphenyl)quinoline 1-oxide (3q)
Yellow solid, mp 172-173 oC (EtOAc). IR (KBr) ν(cm-1): 3126, 1608, 1518, 1400. 1H NMR (400 MHz,
CDCl3) δ: 8.69 (d, JH-H = 8.8 Hz, 1H), 8.07 (s, 1H), 7.80-7.74 (m, 2H), 7.65 (t, JH-H = 7.2 Hz, 1H), 7.44
(d, JH-H = 8.6 Hz, 1H), 7.06 (d, JH-H = 8.6 Hz, 2H), 3.88 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 160.3,
146.2, 141.4, 131.0 (CH), 130.6 (CH), 129.4 (CH), 129.1, 128.4 (CH), 127.1 (CH), 125.3, 120.5 (CH),
+
117.7, 114.0 (CH), 55.3 (CH3). HR MS (ESI) m/z: 330.0126 [M + H]+ (calcd for C16H13BrNO2
330.0124).
4.2.18. 2-(4-Methoxyphenyl)-4-methylquinoline 1-oxide (3r)
Colorless solid, mp 73-74 oC (EtOAc). IR (KBr) ν(cm-1): 2927, 2831, 1599, 1502, 1171. 1H NMR (400
MHz, CDCl3) δ: 8.15-8.11 (m, 3H), 7.96 (d, JH-H = 8.3 Hz, 1H), 7.71-7.66 (m, 2H), 7.50 (td, JH-H = 8.1
Hz, JH-H = 1.1 Hz, 1H), 7.03 (d, JH-H = 8.8 Hz, 2H), 3.87 (s, 3H), 2.74 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ: 160.7, 156.6, 148.1, 144.6, 132.3, 130.0 (CH), 129.2 (CH), 128.8 (CH), 127.0, 125.6 (CH),
123.6 (CH), 119.3 (CH), 114.1 (CH), 55.4 (CH3), 19.0 (CH3). HR MS (ESI) m/z: 266.1174 [M + H]+
(calcd for C17H16NO2+ 266.1176).
4.2.19. 6-Bromo-2-(4-methoxyphenyl)quinoline 1-oxide (3s)
Yellow solid, mp 182-183 oC (EtOAc). IR (KBr) ν(cm-1): 3128, 1609, 1520, 1405, 1215. 1H NMR (400
MHz, CDCl3) δ: 8.72 (d, JH-H = 9.2 Hz, 1H), 8.02-8.00 (m, 3H), 7.82 (dd, JH-H = 9.2 Hz, JH-H = 1.9 Hz,
1H), 7.62 (d, JH-H = 8.8 Hz, 1H), 7.54 (d, JH-H = 8.8 Hz, 1H), 7.04 (d, JH-H = 8.8 Hz, 2H), 3.88 (s, 3H).
13C NMR (100 MHz, CDCl3) δ: 160.7, 144.9, 141.2, 133.7 (CH), 131.2 (CH), 130.3, 129.8 (CH), 125.1,
124.3 (CH), 123.9 (CH), 122.4 (CH), 122.2, 113.7 (CH), 55.4 (CH3). HR MS (ESI) m/z: 330.0126 [M +
H]+ (calcd for C16H13BrNO2+ 330.0124).
4.2.20. 6-Methoxy-2-phenylquinoline 1-oxide (3t)
Light yellow solid, mp 168-169 oC (chloroform) [lit17 mp 176-177 oC]. IR (KBr) ν(cm-1): 2954, 2916,
1624, 1562, 1456, 1196. 1H NMR (400 MHz, CDCl3) δ: 8.75 (d, JH-H = 9.5 Hz, 1H), 7.93 (d, JH-H = 7.1
Hz, 2H), 7.61 (d, JH-H = 8.7 Hz, 1H), 7.49 (t, JH-H = 7.0 Hz, 2H), 7.45-7.42 (m, 2H), 7.38 (dd, JH-H = 9.5
Hz, JH-H = 2.6 Hz, 1H), 7.09 (d, JH-H = 2.6 Hz, 1H), 3.92 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 159.2,
14

ACCEPTED MANUSCRIPT
143.2, 137.8, 133.5, 130.9, 129.5 (CH), 129.2 (CH), 128.2 (CH), 124.3 (CH), 123.8 (CH), 122.5 (CH),
121.9 (CH), 105.8 (CH), 55.7 (CH3). MS (ESI) m/z: 252.2 [M + H]+ (calcd for C16H14NO2+ 252.1).
4.2.21. 2-(tert-butyl)quinoline 1-oxide (3v)
o
o
Pale yellow solid, mp 95-96 C (EtOAc) [lit20 mp 91-92 C]. IR (KBr) ν(cm-1): 3122, 2962, 1560,
1506, 1398, 1334, 1248, 1082. 1H NMR (400 MHz, CDCl3) δ: 8.78 (d, JH-H = 8.8 Hz, 1H), 7.78 (d, JH-H
= 8.0 Hz, 1H), 7.71 (td, JH-H = 8.3 Hz, JH-H = 1.0 Hz, 1H), 7.64 (d, JH-H = 8.9 Hz, 1H), 7.56 (t, JH-H = 7.2
Hz, 1H), 7.44 (d, JH-H = 8.9 Hz, 1H), 1.61 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 154.2, 143.1, 130.3
(CH), 129.1, 127.8 (CH), 127.7 (CH), 125.1 (CH), 120.0 (CH), 119.8 (CH), 36.7, 26.9 (CH3). MS (ESI)
m/z: 202.3 [M + H]+ (calcd for C13H16NO+ 202.1).
4.2.22. 1-phenylisoquinoline-oxide (3w)
o
o
Yellow solid, mp 141-142 C (EtOAc) [lit21 mp 141-143 C]. IR (KBr) ν(cm-1): 3102, 1547, 1504,
1
1378, 1325, 1238. H NMR (400 MHz, CDCl3) δ: 8.29 (d, JH-H = 7.2 Hz, 1H), 7.82 (d, JH-H = 8.0 Hz,
1H), 7.69 (d, JH-H = 7.2 Hz, 1H), 7.61-7.45 (m, 8H). 13C NMR (100 MHz, CDCl3) δ: 146.2, 137.3 (CH),
130.8, 130.1 (CH), 129.5, 129.4 (CH), 129.2, 129.1 (CH), 128.7 (CH), 128.4 (CH), 126.8 (CH), 125.7
(CH), 123.4 (CH). MS (ESI) m/z: 202.2 [M + H]+ (calcd for C15H12NO+ 222.0).
4.2.23. 1-(p-tolyl)isoquinoline 2-oxide (3x)
o
o
Yellow solid, mp 165-166 C (EtOAc) [lit8a mp 166-167 C]. IR (KBr) ν(cm-1): 3057, 1620, 1550,
1498, 817. 1H NMR (400 MHz, CDCl3) δ: 8.28 (d, JH-H = 7.2 Hz, 1H), 7.80 (d, JH-H = 8.0 Hz, 1H), 7.66
(d, JH-H = 7.2 Hz, 1H), 7.57-7.53 (m, 1H), 7.51-7.48 (m, 2H), 7.43-7.38 (m, 4H), 2.47 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ: 146.4, 139.4, 137.3 (CH), 130.0 (CH), 129.6, 129.5 (CH), 129.2, 129.0
(CH), 128.3 (CH), 127.8, 126.8 (CH), 125.9 (CH), 123.2 (CH), 21.5 (CH3). MS (ESI) m/z: 236.3 [M +
H]+ (calcd for C16H14NO+ 236.1).
4.3 The procedure for the deoxygenation of 2-(4-methoxyphenyl)quinoline N-oxide
2-arylquinoline N-oxide 3f (0.2 mmol, 50.2 mg), Pd(OAc)2 (5 .0 mmol%, 3.2 mg), and dppf
(5.0 mmol%, 8.0 mg) were placed in a 5.0 mL microwave tube, then dry CH3CN (3.0 mL)
o
and Et3N (0.6 mmol, 60.6 mg) were added. The reaction mixture was heated at 120 C by
microwave irradiation for 1.0 h. The solvent was concentrated under reduced pressure.
The crude product was purified by silica gel column chromatography to give the desired
products 3f’ using ethyl acetate/petroleum ether (1:8) as eluant.
2-(4-Methoxyphenyl)quinoline (3f’)
15

ACCEPTED MANUSCRIPT
Yellow crystal, mp 113-114 oC (from EtOAc; lib.22 118-119 oC). 1H NMR (400 MHz, CDCl3) δ: 8.17 (d,
JH-H = 8.7 Hz, 1H), 8.13 (d, JH-H = 8.8 Hz, 2H), 7.83 (d, JH-H = 8.6 Hz, 1H), 7.80 (d, JH-H = 8.2 Hz, 1H),
7.71 (td, JH-H = 8.3 Hz, JH-H = 1.3 Hz, 1H), 7.49 (td, JH-H = 8.0 Hz, JH-H = 1.0 Hz, 1H), 7.04 (d, JH-H = 8.6
Hz, 2H), 3.88 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 160.8, 156.9, 148.2, 136.6 (CH), 132.2, 129.5
(CH), 129.4 (CH), 128.9 (CH), 127.4 (CH), 126.9, 125.9 (CH), 118.5 (CH), 114.2 (CH), 55.4 (CH3). IR
(KBr) ν(cm-1): 2956, 1655, 1597, 1498. HR MS (ESI) m/z: 236.1074 [M + H]+ (calcd for C16H14NO+
236.1070).
Acknowledgement
We gratefully acknowledge the National Natural Science Foundation of China (No. 21172055 and
21302042), Department of Henan Province Natural Science and Technology Foundation (No.
142102210410), Natural Science Foundation in Henan Province Department of Education (No.
17A150005), the Program for Innovative Research Team from Zhengzhou (No. 131PCXTD605). We
also thank Prof. Dr. Donghui Wei (College of Chemistry and Molecular Engineering, Zhengzhou
University) for his the assistance of DFT calculations.
References and notes
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