Cu(OAc)2-catalyzed direct radical C2 arylation of quinoline N-oxide with arylamines

Article abstract of DOI:10.1016/j.tet.2017.03.009

A Cu(OAc)₂-catalyzed synthesis of 2-arylquinoline N-oxides with easily available arylamines is described. The main features of this reaction are mild reaction conditions, high functional-group tolerance, excellent regioselectivity, and good to excellent yields. This procedure is mild, operationally simple, and constitutes a greener approach to the arylation of quinoline N-oxides.

Full text of DOI:10.1016/j.tet.2017.03.009

Accepted Manuscript
Cu(OAc) -catalyzed direct radical C2 arylation of quinoline N-oxide with arylamines
2
Jin-Wei Yuan, Shuai-Nan Liu, Ling-Bo Qu
PII:
S0040-4020(17)30234-X
10.1016/j.tet.2017.03.009
TET 28515
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 February 2017
Accepted Date: 3 March 2017
Please cite this article as: Yuan J-W, Liu S-N, Qu L-B, Cu(OAc) -catalyzed direct radical C2 arylation of
2
quinoline N-oxide with arylamines, Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.009.
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ACCEPTED MANUSCRIPT
Cu(OAc)2-catalyzed direct radical C2 arylation of quinoline N-oxide
with arylamines
Jin-Wei Yuan,1,* Shuai-Nan Liu,2 Ling-Bo Qu1
1. School of Chemistry & Chemical Engineering, Henan University of Technology; Academician
Workstation for Natural Medicinal Chemistry of Henan Province, Zhengzhou 450001, P.R. China
2.
School of Biological Engineering, Henan University of Technology, Zhengzhou 450001, P.R.
China
An efficient protocol for the synthesis of 2-arylquinoline N-oxides has been developed via
Cu(OAc)2-catalyzed cross-coupling reaction of quinoline N-oxides with arylamines in mild
conditions with moderated to good yields.

ACCEPTED MANUSCRIPT
Cu(OAc)2-catalyzed direct radical C2 arylation of quinoline N-oxide
with arylamines
Jin-Wei Yuan,1,* Shuai-Nan Liu,2 Ling-Bo Qu1,*
1. School of Chemistry & Chemical Engineering, Henan University of Technology; Academician
Workstation for Natural Medicinal Chemistry of Henan Province, Zhengzhou 450001, P.R. China
2.
School of Biological Engineering, Henan University of Technology, Zhengzhou 450001, P.R.
China
Abstract: A Cu(OAc)2-catalyzed synthesis of 2-arylquinoline N-oxides with easily available
arylamines is described. The main features of this reaction are mild reaction conditions, high
functional-group tolerance, excellent regioselectivity, and good to excellent yields. This procedure
is mild, operationally simple, and constitutes a greener approach to the arylation of quinoline
N-oxides.
Key words: quinoline N-oxide; arylamine; Cu(OAc)2-catalyzed; radical reaction; arylation
1. Introduction
Quinoline and quinoline N-oxides have been widely found in natural products, pharmaceuticals,
and material chemistry.[1] 2-Arylquinoline N-oxide derivatives are important structural motifs
with applications in the areas of drug discovery.[2] Therefore, the efficient and regioselective
construction of C−C bond to quinolines has attracted interest of chemists and pharmacologists. In
particular, introduction of aryl substituent to the C2-position of quinoline derivatives is an
important strategy in heterocyclic synthesis that represents a significant synthetic challenge. As a
result, considerable efforts have been made towards their synthesis and functionalization.
Transition-metal catalyzed C−H arylations of heteroarenes with haloarenes have recently
attracted considerable attentions as such an approach allows the preparation of ubiquitous
structures.[3] Of the methods available for the synthesis of 2-arylquinoline derivatives, the
Pd-catalyzed Suzuki-Miyaura type coupling reaction is one of the most convenient methods for
preparing biaryl compounds.[4] 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
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ligand, K2CO3 for the base in toluene; Ackermam’s group reported a direct arylation of
electron-deficient quinoline 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 a).[5] However, the common limitations of most of these methods are inevitability of
transition-metal palladium which possess high cost and toxicity, prefunctionalization of 2-position
of quinoline N-oxides, expensive arylating counterparts such as boronic acid, elevated
temperature (110-150 oC), and longer reaction time (12-16 h). Transition-metal-free reactions are
of great interest in terms of atom economy, environmental impact, and cost reduction. In 2015,
Antonchick’s group described a direct C-H bond functionalization of quinoline N-oxides to
2-arylated quinoline derivatives by employing quinoline N-oxides with arylboronic acids as
o
substrates, and this transformation was realized without metal in DMSO solvent at 110 C for
2-24 h (Scheme 1, b).[6] Although this method could make a direct arylation of quinoline
N-oxides, and achieve an improved regioselectivity, a high reaction temperature, long reaction
time, and an excess of arylboronic acid (3.0 eq) were still required. Moreover, the scope of the
cross-coupling reaction was limited. In 2016, our group developed a protocol for the synthesis of
2-arylquinoline N-oxides via KMnO4-mediated cross-coupling reaction of quinoline N-oxides with
aromatic hydrazines (Scheme 1, c).[7] Unfortunately, the strong oxidant condition required for
this transformation precluded the arylation of quinoline N-oxides with the reducing groups.
Although significant achievements have been made, a milder and more efficient method for the
synthesis of 2-arylquinoline N-oxides is still in demand.
Previous works:
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This work:
( d )
R2
R2
R1
R1
Cu(OAc)2
+
H2N
N
O
H
N
O
R3
R3
t-BuONO
Scheme 1 Synthesis of 2-arylquinoline N-oxides
Aryl diazonium salts are traditionally used in their tetrafluoroborate form as crystalline salts but
their high reactivity and hazardous profile make these compounds unsuitable for safe handling,
especially on a large scale.[8] Aryl amines are known to be easily accessible as well as relatively
safe and highly stable, and are hence common synthons in transitional metal-catalyzed coupling
reactions and non-metal-mediated transformations.[9] Usually, direct transformations of anilines
involve cleavage of C−N bonds in anilines, and the amino group acts as a formal leaving group in
the process. Here, diazonium salts are generated as the key intermediates via an in situ strategy
without being isolated. By employing tert-butyl nitrite and related compounds as diazotizing
reagents, and the direct transformations of anilines have been successfully accomplished in the
presence of metal salts and non-metal conditions.[10] On the other hand, free-radical C-H
arylation of heteroarenes through both metal- and non-metal-mediated processes has emerged
as a valuable alternative enabling application of mild conditions.[11] Among others, aryl
diazonium salts are well known species giving free-radical aryl intermediates through a
heterolytic dediazoniation mechanism.[12] Recently palladium or copper-catalyzed processes
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involving aryl diazonium salts, known as the Meerwein-type arylation has reported on highly
sensitive quinines, and pyrroles under unusual and safe conditions.[13] Inspired by these studies
and our continuing interest in the arylation of heterocyclic scaffolds, herein, we reported an
unprecedented and direct copper-catalyzed regioselective arylation of quinoline N-oxides with in
situ generated aryl diazonium salts under neutral conditions in aqueous solvents (Scheme 1, d).
2. Results and discussion
Initially, the reaction of quinoline N-oxide (1a) with aniline (2a) was examined through an in situ
generated aryl diazonium salt with tert-butyl nitrite (t-BuONO). During our optimization studies,
we assessed various copper catalysts in CH3CN at room temperature for 2.0 h (Table 1, Entries
1-6), which Cu(OAc)2 5H2O emerged as the best one to give the product (3a) with a 50% yield,
and CuCl and CuI2 could also make better yields (45% and 47%). The structure of 3a was
elucidated through IR, MS and NMR, and the arylation reaction was proceeded at C2 position of
quinoline N-oxide with high regioselectivity. In the following study, 0.15 equiv was found to be
the ideal amount of Cu(OAc)2 5H2O and the yield of 3a was 54% (Table 1, Entries 6-9). Among the
solvents screened such as CH3CN, DMSO, acetone, CH2Cl2, CH3OH, H2O, and co-solvents, the
co-solvent of acetone/H2O (2:1) was proven to be the best choice for this reaction (Table 1,
Entries 10-20). In order to avoid the formation of any acid-mediated azo compound, some mild
bases including Na2CO3, K2CO3, Cs2CO3, NaOAc, and CaCO3 were used in this reaction. The result
showed that the yield of 3a was about 60%, and other side-product would decrease obviously
when CaCO3 was used (Table 1, Entries 21-25). This result hints at a twofold role for CaCO3 since it
acts as a buffer additive suppressing the formation of azo compounds but also steps into the
catalytic cycle to improve the reaction efficiency. The effect of reaction temperature was also
o
o
investigated. By increasing the reaction temperature from 20 C to 50 C, the yield of 3a was
dramatically increased to 73% (Table 1, Entries 25-28). As most aryl diazonium salts are very
unstable and sometimes explosive above 0 oC, herein the reaction temperature only increased to
o
50 C. The reaction time was also examined, and 1.5 h proved to be the ideal time. If the time
was prolonged, the side-product would be increased and the yield of 3a would decrease a little
(Table 1, Entries 28-31). Finally, the ratio of quinoline N-oxide with aniline was investigated, and
the ratio 1:1 of quinoline N-oxide with aniline proved to be the best result, providing 75% yield of
3a (Supporting information, Table S1, entries 1-5). In the absence of the catalyst Cu(OAc)2 5H2O,
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the desired product was only obtained 20% yield (Table 1, Entry 32), and the result showed that
Cu(OAc)2 5H2O played an important role for this cross-coupling reaction. Consequently, the
optimum reaction conditions were determined to be the ratio of quinoline N-oxide, aniline with
tert-butyl nitrite (1:1:1), Cu(OAc)2 5H2O (0.15 equiv) for the catalyst, CaCO3 (1.0 equiv) in
acetone/H2O (2:1) at 50 oC for 1.5 h (Table 1, Entry 31).
Table 1 Optimization of reaction conditionsa
t-BuONO
+ H2N
N
O
H
N
O
1a
2a
3a
Temp Time Yieldb
Entry
1
Catalyst (eq.)
CuBr (0.1)
Base
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
Acetone
CH2Cl2
CH3OH
H2O
(oC)
(h)
(%)
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
20
2.0
24
2
CuCl (0.1)
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
45
30
47
33
50
36
54
52
18
49
20
48
nrc
20
Trace
< 5
35
3
CuCl2 (0.1)
4
CuI2 (0.1)
5
CuSO4 5H2O (0.1)
Cu(OAc)2 5H2O (0.1)
Cu(OAc)2 5H2O (0.05)
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.2)
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
6
7
8
9
10
11
12
13
14
15
16
17
18
DMSO/H2O
=1:1
CH2Cl2/H2O
=1:1
CH3OH/H2O
=1:1
Acetone/H2O
=1:1
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Acetone/H2O
=2:1
Acetone/H2O
=3:1
acetone/H2O
=2:1
acetone/H2O
=2:1
acetone/H2O
=2:1
acetone/H2O
=2:1
acetone/H2O
=2:1
acetone/H2O
=2:1
acetone/H2O
=2:1
acetone/H2O
=2:1
acetone/H2O
=2:1
acetone/H2O
=2:1
acetone/H2O
=2:1
acetone/H2O
=2:1
19
20
21
22
23
24
25
26
27
28
29
30
31
32d
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
/
/
20
20
20
20
20
20
20
30
40
50
50
50
50
50
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
0.5
1.0
1.5
1.5
56
54
50
55
58
52
60
63
68
73
60
65
75
20
Cu(OAc)2 5H2O (0.15) Na2CO3
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
Cu(OAc)2 5H2O (0.15)
/
K2CO3
Cs2CO3
NaOAc
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
a
Reaction conditions: quinoline N-oxide 1a (0.3 mmol, 43.5 mg), aniline 2a, t-BuONO (0.36 mmol, 37.1 mg),
Cu(OAc)2 5H2O (0.045 mmol, 12.2 mg) as the catalyst, CaCO3 (0.3 mmol, 30 mg) in acetone/H2O = 2:1 (3.0 mL)
co-solvent, at 50 oC for 1.5 h.
b Isolated yield.
c nr = no reaction.
d
No catalyst was added.
With the optimized conditions in hand (Table 1, Entry 31), the scope of the reaction was
undertaken by investigating the reaction of quinoline N-oxides (1) with arylamines (2), as shown
in Table 2. First, the effect of the substitution pattern on the aryl ring of arylamines was examined.
Both electron-donating (2a-2e) and electron-withdrawing (2f-2p) groups on the phenyl ring
produced the corresponding 3-aryl quinoline N-oxides (3a-3p) in moderated to good yields
(49-82%). Moreover, arylamines bearing electron-donating groups could give better yields
(68-82%) than those with electron-withdrawing groups (49-74%). Gratifyingly, arylamines with
strong electron-deficient groups –CN, and –NO2 could also reacted smoothly with quinoline
N-oxide to give the corresponding products 3n and 3p with better yields (71% and 69%). In
addition, the halogen containing-motifs, such as –F (3f), -Cl (3g, 3j-3l), -Br (3h), and –I (3i), were
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compatible despite the free-radical conditions, opening the door for further functionalization. It
was noteworthy that heterocyclic aromatic amine, methyl 3-aminothiophene-2-carboxylate (2q),
was well tolerated to give the product 3q with 75% yield. The products 3e and 3j were obtained
with 68% and 56% yields, respectively. Unfortunately, there was no desired product detected
when naphthalen-1-amine was employed. Remarkably, the electronic and steric hindrance effects
of coupling partner aromatic amines have some influence on the success of the coupling
reaction.
Table 2 Synthesis of 2-arylquinoline N-oxides from quinoline N-oxides and arylaminesa,b
N
O
N
O
N
O
3a
3b
3c
(81%)
(75%)
(80%)
O
N
O
N
O
N
O
O
F
3d
3e
3f
(53%)
(82%)
(68%)
N
O
N
O
N
O
Cl
Br
Cl
I
3g
3h
3i
(52%)
(51%)
(49%)
Cl
Cl
N
O
N
O
N
O
Cl
3j
3k
3l
(55%)
(56%)
(57%)
7

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a
Reaction conditions: quinoline N-oxides 1 (0.3 mmol), aniline 2a (0.3 mmol), t-BuONO (0.36 mmol, 37.1 mg),
Cu(OAc)2 5H2O (0.045 mmol, 12.2 mg) as the catalyst, CaCO3 (0.3 mmol, 30 mg) in acetone/H2O = 2:1 (3.0 mL)
co-solvent, at 50 oC for 1.5 h.
b Isolated yield.
Next, the reactions of various quinoline N-oxides with 4-methoxyaniline were examined (Table 2).
We were pleased to find that quinoline N-oxides bearing either electron-donating (-CH3, -OCH3)
or electron-withdrawing (-Cl, -Br) groups at the 4, 6, or 8 positions of the aromatic ring were
compatible with the optimized conditions (3s-3w, 3y). Unfortunately, 6-nitroquinoline N-oxide
failed to react with 4-methoxyaniline under the optimized reaction conditions. However,
3-bromoquinoline N-oxide reacted with 4-methoxyaniline to afford 3z in 80% yield, suggesting
that the steric effect of quinoline N-oxides plays a weak influence on the reaction. To further
investigate the versatility of this method, isoquinoline N-oxide was employed. Interestingly, the
transformation was regioselective, and the ratio of C1-arylated and C3-arylated isoquinoline
N-oxides were about 3:1.
Further usefulness of this methodology was demonstrated by the successful C-H arylation of
quinoline N-oxides. 2-Arylquinoline skeletons are of particular importance for the construction of
a wide range of biologically active molecules.[14] With these impressive results, this
transition-metal Cu(OAc)2-catalyzed arylation was also tested on other heterocycles such as
quinolines. Under similar conditions to that of quinolines, this reaction was also effective (Table
3). Quinolines could react smoothly with aryl amines to provide the corresponding products
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5a-5d in 37-72% yields. Compared with quinoline N-oxides, the yield of this reaction decreased
slightly when the nonoxide quinolines were employed as the reaction substrates. For example,
the yield of 3y was 79%, and the yield of 5b decreased to 72%. Herein, the N−O group of
quinoline N-oxides was essential for the arylation, presumably because the oxidation of
quinolines enhances the reactivity of quinoline N-oxides towards capturing nucleophilic aryl
group. However, in cases for which there are two possible reactive sites, as in the case of the C4
position unsubstituted quinolines, a minor amount of the C4-arylated product was also formed
(Table 3, 5d and 5d′).
Table 3 Synthesis of 2-arylquinolines from quinolines and aryl aminesa,b
a
Reaction conditions: quinolines 4 (0.3 mmol), aryl amines 2 (0.3 mmol), t-BuONO (0.36 mmol, 37.1 mg),
Cu(OAc)2 5H2O (0.045 mmol, 12.2 mg) as the catalyst, CaCO3 (0.3 mmol, 30 mg) in acetone/H2O = 2:1 (3.0 mL)
co-solvent, at 50 oC for 1.5 h.
b Isolated yield.
The preliminary mechanistic investigations on this C-H arylation by using aniline in the presence
of tert-butylnitrite suggests a radical mechanism analogous to that proposed by Felpin et al.[15]
When the arylation of quinoline N-oxide 1a with aniline 2a was conducted in the presence of the
radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (1.0 equiv.), the yield of 3a
decreased to 21%. The expected coupling product 3a was not formed when 2.0 equiv. TEMPO
was added. Moreover, the effect of another radical scavenger 2,4,6-tributylphenol was also
investigated. With 2,4,6-tributylphenol (2.0 equiv.) adding to this reaction, the formation of the
coupled product 3a dramatically decreased to 12%. These results indicated that the reaction
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might proceed via a radical pathway. On the basis of our experimental observations and with
assistance from the literatures,[16] the following catalytic cycle should account for the
mechanism involved in this transformation (Scheme 2). In the presence of t-BuONO, aniline 2a
would be transformed into its corresponding diazonium salt A,[15c,17] which was believed to
generate the highly reactive phenyl radical B using a Cu(I) as a catalyst. Quickly the radical B was
intercepted by the quinoline N-oxide 1a to produce the radical intermediate C. Subsequently, the
intermediate C was further oxidized by Cu(II) species into the corresponding cation D, which upon
deprotonation provides the expected coupling product 3a. The role of CaCO3 was important for
this coupling reaction because it could facilitate the deprotonation of the quinoline N-oxide
cation D, which likely follows undesirable pathways decreasing the reaction yield in the absence
of a base.
Scheme 2 Proposed the reaction mechanism
3. Conclusion
In summary, we have developed an efficient and regioselective Meerwein-type arylation of
quinoline N-oxides under very mild conditions. The methodology features aqueous solvents,
inexpensive reagents and catalysts, as well as experimental simplicity.
4. Experimental
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4.1 General information
Anhydrous solvents were obtained by standard procedure. All substrates purchased from J & K
Scientific Ltd. were used without further purification. Column chromatography was performed
using 200–300 mesh silica with the indicated solvent system according to standard techniques.
Analytical thin-layer chromatography (TLC) was performed on precoated, glassbacked silica gel
plates. Visualization of the developed chromatogram was performed by UV absorbance (254 nm
or 365 nm). Nuclear magnetic resonance spectra were recorded on Bruker Avance 400 MHz
spectrometer. Chemical shifts for 1H 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 permillion 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 procedure for synthesis of 2-arylquinoline N-oxide derivatives 3
In a 25 mL Schlenk tube, quinoline N-oxides 1 (0.3 mmol), arylamines 2 (0.3 mmol), tert-butyl
nitrite (0.36 mmol, 37.1 mg), and Cu(OAc)2 5H2O (0.045 mmol, 12.2 mg) as a catalyst in
o
acetone/H2O (3.0 mL) were added and the reaction was stirred at 50 C for 1.5 h (monitored by
TLC). The reaction mixture was diluted with ethyl acetate, and saturated sodium chloride
solution washed three times. The resulting organic phase was dried over anhydrous Na2SO4 and
concentrated under vacuum. The crude product was purified by silica gel column
chromatography using ethyl acetate/petroleum ether (1 : 3 to 2 : 1) as eluant to obtain the
desired products 3.
4.2.1 2-Phenylquinoline 1-oxide (3a)
o
o
Colorless solid, mp 145-146 C (EtOAc) [lit5a mp 148.5-149.7 C]. IR (KBr) ν(cm-1): 1462, 1377,
1352, 1302. 1H NMR (400 MHz, CDCl3) δ: 8.86 (d, JH-H = 8.8 Hz, 1H), 7.97 (d, JH-H = 7.2 Hz, 2H), 7.86
(d, JH-H = 8.1 Hz, 1H), 7.80-7.73 (m, 2H), 7.64 (t, JH-H = 7.6 Hz, 1H), 7.54-7.44 (m, 4H). 13C NMR (100
MHz, CDCl3) δ: 145.1, 142.3, 133.4, 130.6 (CH), 129.6 (CH), 129.5 (CH), 128.4 (CH), 128.3 (CH),
127.9 (CH), 125.3 (CH), 123.3 (CH), 120.3 (CH). MS (ESI) m/z: 222.3 [M + H]+ (calcd for C15H12NO+
11

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222.1).
4.2.2 2-(p-Tolyl)quinoline 1-oxide (3b)
o
o
Colorless solid, mp 125-126 C (EtOAc) [lit5a 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 = 8.8 Hz, 1H), 7.89 (d, JH-H = 8.1 Hz, 2H), 7.85 (d,
JH-H = 8.1 Hz, 1H), 7.80-7.73 (m, 2H), 7.63 (t, JH-H = 7.4 Hz, 1H), 7.51 (d, JH-H = 8.7 Hz, 1H), 7.33 (d,
JH-H = 7.9 Hz, 2H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 145.2, 142.3, 139.8, 130.6 (CH), 130.5,
129.5 (CH), 129.4, 129.0 (CH), 128.3 (CH), 127.9 (CH), 125.4 (CH), 123.3 (CH), 120.2 (CH), 21.5
(CH3). MS (ESI) m/z: 236.3 [M + H]+ (calcd for C16H14NO+ 236.1).
4.2.3 2-(4-Ethylphenyl)quinoline 1-oxide (3c)
Yellow solid, mp 96-97 oC (EtOAc) [lit7 mp 108-109 oC]. IR (KBr) ν(cm-1): 3124, 3082, 1601, 1450.
1H NMR (400 MHz, CDCl3) δ: 8.86 (d, JH-H = 8.8 Hz, 1H), 7.93 (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 = 7.5 Hz,
JH-H = 0.8 Hz, 1H), 7.51 (d, JH-H = 8.7 Hz, 1H), 7.36 (d, JH-H = 8.2 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, 145.2, 142.3, 130.7, 130.5 (CH),
129.6 (CH), 129.4, 128.2 (CH), 127.9 (CH), 127.8 (CH), 125.3 (CH), 123.3 (CH), 120.3 (CH), 28.8
(CH2), 15.4 (CH3). MS (ESI) m/z: 250.2 [M + H]+ (calcd for C17H16NO+ 250.1).
4.2.4 2-(4-Methoxyphenyl)quinoline 1-oxide (3d)
o
o
Yellow solid, mp 105-106 C (EtOAc) [lit5a mp 124.9-126.0 C]. IR (KBr) ν(cm-1): 3122, 2931, 1604,
1
1560, 1500, 1400. H NMR (400 MHz, CDCl3) δ: 8.82 (d, JH-H = 8.8 Hz, 1H), 8.00 (d, JH-H = 8.9 Hz,
2H), 7.78 (d, JH-H = 8.0 Hz, 1H), 7.72 (td, JH-H = 7.9 Hz, JH-H = 1.2 Hz, 1H), 7.67 (d, JH-H = 8.7 Hz, 1H),
7.56 (td, JH-H = 7.5 Hz, JH-H = 1.0 Hz, 1H), 7.46 (d, JH-H = 8.7 Hz, 1H), 7.00 (d, JH-H = 8.9 Hz, 2H), 3.84
(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), 113.7 (CH), 55.3 (CH3). MS (ESI) m/z:
252.3 [M + H]+ (calcd for C16H14NO2+ 252.1).
4.2.5 2-(2-Methoxyphenyl)quinoline 1-oxide (3e)
o
o
Yellow solid, mp 144-145 C (EtOAc) [lit18 mp 182-184 C]. IR (KBr) ν(cm-1): 3070, 2922, 1560,
1
1452, 1340, 1248, 822. H NMR (400 MHz, CDCl3) δ: 8.83 (d, JH-H = 8.7 Hz, 1H), 7.86 (d, JH-H = 7.8
Hz, 1H), 7.76-7.60 (m, 2H), 7.52 (dd, JH-H = 7.5 Hz, JH-H = 2.6 Hz, 1H), 7.47-7.39 (m, 2H), 7.11-7.03
(m, 2H), 3.80 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 157.2, 143.9, 142.1, 130.8 (CH), 130.7 (CH),
130.1 (CH), 129.8, 128.2 (CH), 127.9 (CH), 124.4 (CH), 124.2 (CH), 122.9, 120.6 (CH), 120.3 (CH),
12

ACCEPTED MANUSCRIPT
111.3 (CH), 55.8 (CH3). MS (ESI) m/z: 252.3 [M + H]+ (calcd for C16H14NO2+ 252.1).
4.2.6 2-(4-Fluorophenyl)quinoline 1-oxide (3f)
Light yellow solid, mp 157-159 oC (EtOAc) [lit5b mp 162-164 oC]. IR (KBr) ν(cm-1): 1603, 1564, 1498,
1458, 1321, 1230, 814. 1H NMR (400 MHz, CDCl3) δ: 8.84 (d, JH-H = 8.8 Hz, 1H), 8.03-7.99 (m, 2H),
7.87 (d, JH-H = 8.0 Hz, 1H), 7.81-7.75 (m, 2H), 7.65 (td, JH-H = 7.5 Hz, JH-H = 0.8 Hz, 1H), 7.49 (d, JH-H
= 8.7 Hz, 1H), 7.21 (t, JH-H = 8.7 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ: 163.2 (d, JF-C = 249.0 Hz),
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).
4.2.7 2-(4-Chlorophenyl)quinoline 1-oxide (3g)
Brown solid, mp 182-184 oC (EtOAc) [lit5c mp 172-174 oC]. IR (KBr) ν(cm-1): 1558, 1467, 1334, 812.
1H NMR (400 MHz, CDCl3) δ: 8.83 (d, JH-H = 8.8 Hz, 1H), 7.95 (d, JH-H = 8.5 Hz, 2H), 7.86 (d, JH-H = 8.0
Hz, 1H), 7.81-7.74 (m, 2H), 7.65 (t, JH-H = 7.3 Hz, 1H), 7.49-7.46 (m, 3H). 13C NMR (100 MHz, CDCl3)
δ: 143.8, 142.2, 135.5, 131.8, 131.0 (CH), 130.7 (CH), 129.6, 128.6 (CH), 128.5 (CH), 128.0 (CH),
125.4 (CH), 122.9 (CH), 120.2 (CH). MS (ESI) m/z: 256.1 [M + H]+ (calcd for C15H11ClNO+ 256.0).
4.2.8 2-(4-Bromophenyl)quinoline 1-oxide (3h)
Brown solid, mp 183-184 oC (EtOAc) [lit7 mp 183-184 oC]. IR (KBr) ν(cm-1): 1552, 1502, 1336, 808.
1H NMR (400 MHz, CDCl3) δ: 8.84 (d, JH-H = 8.8 Hz, 1H), 7.90-7.86 (m, 3H), 7.82-7.75 (m, 2H),
7.68-7.64 (m, 3H), 7.48 (d, JH-H = 8.7 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). MS (ESI) m/z: 300.0 [M + H]+ (calcd for C15H11BrNO+ 300.0).
4.2.9 2-(4-Iodophenyl)quinoline 1-oxide (3i)
Yellow solid, mp 169-170 oC (EtOAc). IR (KBr) ν(cm-1): 2954, 2924, 1662, 1550. 1H NMR (400 MHz,
CDCl3) δ: 8.83 (d, JH-H = 8.5 Hz, 1H), 7.87-7.81 (m, 3H), 7.79-7.73 (m, 4H), 7.65 (t, JH-H = 7.5 Hz, 1H),
7.47 (d, JH-H = 8.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 144.0, 142.3, 137.5 (CH), 132.9, 131.2
(CH), 130.7 (CH), 129.6, 128.6 (CH), 128.0 (CH), 125.3 (CH), 122.8 (CH), 120.2 (CH). HR MS (ESI)
m/z: 347.9882 [M + H]+ (calcd for C15H11INO+ 347.9880).
4.2.10 2-(2-Chlorophenyl)quinoline 1-oxide (3j)
Yellow solid, mp 107-108 oC (EtOAc) [lit5a mp 106-107 oC]. IR (KBr) ν(cm-1): 1558, 1566, 1346, 685.
1H NMR (400 MHz, CDCl3) δ: 8.84 (d, JH-H = 8.7 Hz, 1H), 7.91 (d, JH-H = 8.0 Hz, 1H), 7.81-7.76 (m,
13

ACCEPTED MANUSCRIPT
2H), 7.68 (t, JH-H = 7.6 Hz, 1H), 7.57-7.51 (m, 2H), 7.45-7.41 (m, 3H). 13C NMR (100 MHz, CDCl3) δ:
144.0, 142.0, 133.8, 133.1, 131.0 (CH), 130.6 (CH), 130.5 (CH), 130.1, 129.8 (CH), 128.7 (CH),
128.0 (CH), 126.9 (CH), 124.7 (CH), 123.6 (CH), 120.3 (CH). MS (ESI) m/z: 256.2 [M + H]+ (calcd for
C15H11ClNO+ 256.0).
4.2.11 2-(3-Chlorophenyl)quinoline 1-oxide (3k)
Yellow solid, mp 141-142 oC (EtOAc). IR (KBr) ν(cm-1): 1566, 1448, 1340, 1242, 1063, 822. 1H NMR
(400 MHz, CDCl3) δ: 8.83 (d, JH-H = 8.8 Hz, 1H), 8.00 (s, 1H), 7.89-7.76 (m, 4H), 7.66 (t, JH-H = 7.4 Hz,
1H), 7.49-7.44 (m, 3H). 13C NMR (100 MHz, CDCl3) δ: 143.7, 142.2, 135.0, 134.2, 130.8 (CH), 129.7,
129.6 (CH), 129.5 (CH), 128.7, 128.0 (CH), 127.7 (CH), 125.4 (CH), 122.9 (CH), 120.2 (CH). HR MS
(ESI) m/z: 256.0522 [M + H]+ (calcd for C15H11ClNO+ 256.0524).
4.2.12 2-(3,5-Dichlorophenyl)quinoline 1-oxide (3l)
o
1
Yellow solid, mp 150-151 C (EtOAc). IR (KBr) ν(cm-1): 1550, 1327, 866, 804. H NMR (400 MHz,
CDCl3) δ: 8.81 (d, JH-H = 8.8 Hz, 1H), 7.90-7.88 (m, 3H), 7.81-7.77 (m, 2H), 7.68 (t, JH-H = 7.4 Hz, 1H),
7.46 (dd, JH-H = 8.8 Hz, JH-H = 4.6 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ: 148.1, 142.2, 136.0, 134.9,
131.0 (CH), 129.8, 129.5 (CH), 129.0 (CH), 128.1 (CH), 128.0 (CH), 125.6 (CH), 122.6 (CH), 120.2
(CH). HR MS (ESI) m/z: 290.0132 [M + H]+ (calcd for C15H10Cl2NO+ 290.0134).
4.2.13 2-(4-Acetylphenyl)quinoline 1-oxide (3m)
o
Yellow solid, mp 176-177 C (EtOAc). IR (KBr) ν(cm-1): 2927, 2850, 1664, 1566, 1333, 1275, 804.
1H NMR (400 MHz, CDCl3) δ: 8.85 (d, JH-H = 8.8 Hz, 1H), 8.10 (bs, 4H), 7.90 (d, JH-H = 8.0 Hz, 1H),
7.84-7.78 (m, 2H), 7.68 (t, JH-H = 7.2 Hz, 1H), 7.52 (d, JH-H = 8.7 Hz, 1H), 2.67 (s, 3H). 13C NMR (100
MHz, CDCl3) δ: 197.6, 143.9, 142.3, 137.9, 137.4, 130.8 (CH), 129.9 (CH), 129.8, 128.8 (CH), 128.2
(CH), 128.0 (CH), 125.5 (CH), 122.9 (CH), 120.2 (CH), 26.8 (CH3). HR MS (ESI) m/z: 264.1023 [M +
H]+ (calcd for C17H14NO2+ 264.1019).
4.2.14 2-(4-cyanophenyl)quinoline 1-oxide (3n)
o
o
Colorless solid, mp 205-206 C (EtOAc) [lit5c mp 206-208 C]. IR (KBr) ν(cm-1): 2937, 2225, 1312,
817. 1H NMR (400 MHz, CDCl3) δ: 8.82 (d, JH-H = 8.8 Hz, 1H), 8.11 (d, JH-H = 8.4 Hz, 2H), 7.91 (d, JH-H
= 8.0 Hz, 1H), 7.82-7.79 (m, 4H), 7.70 (t, JH-H = 7.3 Hz, 1H), 7.49 (d, JH-H = 8.7 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ: 143.0, 142.2, 137.8, 132.0 (CH), 131.0 (CH), 130.3 (CH), 129.9, 129.1 (CH), 128.1
(CH), 125.6 (CH), 122.6 (CH), 120.2 (CH), 118.5, 112.9. MS (ESI) m/z: 247.2 [M + H]+ (calcd for
C16H11N2O+ 247.0).
14

ACCEPTED MANUSCRIPT
4.2.15 2-(4-(Methoxycarbonyl)phenyl)quinoline 1-oxide (3o)
Yellow solid, mp 169-170 oC (EtOAc). IR (KBr) ν(cm-1): 2942, 1726, 1554, 1286, 1105, 762. 1H NMR
(400 MHz, CDCl3) δ: 8.83 (d, JH-H = 8.7 Hz, 1H), 8.17 (d, JH-H = 7.4 Hz, 2H), 8.05 (d, JH-H = 7.4 Hz, 2H),
7.87 (d, JH-H = 8.0 Hz, 1H), 7.81-7.76 (m, 2H), 7.66 (t, JH-H = 7.4 Hz, 1H), 7.50 (d, JH-H = 8.4 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ: 166.5, 144.0, 142.3, 137.8, 130.7 (CH), 129.8, 129.6 (CH), 129.4 (CH),
128.7 (CH), 128.0 (CH), 125.3 (CH), 123.0 (CH), 120.2 (CH), 52.2 (CH3). HR MS (ESI) m/z: 280.0970
[M + H]+ (calcd for C17H14NO3+ 280.0968).
4.2.16 2-(4-Nitrophenyl)quinoline 1-oxide (3p)
o
o
Yellow needles solid, mp 234-235 C (EtOAc) [lit19 mp 225-226 C]. IR (KBr) ν(cm-1): 1514, 1356,
1250, 1111, 843. 1H NMR (400 MHz, CDCl3) δ: 8.81 (d, JH-H = 8.7 Hz, 1H), 8.34 (d, JH-H = 8.6 Hz, 2H),
8.16 (d, JH-H = 8.6 Hz, 2H), 7.91 (d, JH-H = 8.1 Hz, 1H), 7.83-7.80 (m, 2H), 7.70 (t, JH-H = 7.5 Hz, 1H),
7.51 (d, JH-H = 8.7 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 147.9, 142.8, 142.2, 139.6, 131.1 (CH),
130.7 (CH), 130.0, 129.2 (CH), 128.2 (CH), 125.7 (CH), 123.4 (CH), 122.6 (CH), 120.2 (CH). MS (ESI)
m/z: 267.2 [M + H]+ (calcd for C15H11N2O3+ 267.1).
4.2.17 2-(2-(Methoxycarbonyl)thiophen-3-yl)quinoline 1-oxide (3q)
Yellow solid, mp 157-158 oC (EtOAc). IR (KBr) ν(cm-1): 3107, 3070, 2922, 1709, 1560, 1437, 1267,
1
1068, 754. H NMR (400 MHz, CDCl3) δ: 8.79 (d, JH-H = 8.7 Hz, 1H), 7.88 (d, JH-H = 8.0 Hz, 1H),
7.78-7.72 (m, 2H), 7.66-7.63 (m, 2H), 7.42-7.39 (m, 2H), 3.75 (s, 3H). 13C NMR (100 MHz, CDCl3) δ:
161.7, 141.9, 141.0, 139.0, 131.2, 130.7 (CH), 130.3 (CH), 130.2 (CH), 130.0, 128.6 (CH), 128.0
(CH), 124.3 (CH), 123.9 (CH), 120.1 (CH), 52.2 (CH3). HR MS (ESI) m/z: 286.0534 [M + H]+ (calcd for
C15H12NO3S+ 286.0532).
4.2.18 2-(4-Methoxyphenyl)-6-methylquinoline 1-oxide (3s)
Yellow solid, mp 137-138 oC (EtOAc). IR (KBr) ν(cm-1): 2937, 1560, 1508, 1338, 1176, 814, 675. 1H
NMR (400 MHz, CDCl3) δ: 8.71 (d, JH-H = 9.3 Hz, 1H), 7.96 (d, JH-H = 8.8 Hz, 2H), 7.61-7.55 (m, 3H),
7.43 (d, JH-H = 8.7 Hz, 1H), 7.01 (d, JH-H = 8.8 Hz, 2H), 3.85 (s, 3H), 2.51 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ: 160.4, 144.0, 140.7, 138.3, 132.6 (CH), 131.2 (CH), 129.3, 126.8 (CH), 125.7, 124.9 (CH),
123.0 (CH), 119.9 (CH), 113.6 (CH), 55.3 (CH3), 21.3 (CH3). HR MS (ESI) m/z: 266.1174 [M + H]+
(calcd for C17H16NO2+ 266.1176).
4.2.19 6-Methoxy-2-(4-methoxyphenyl)quinoline 1-oxide (3t)
o
o
Yellow solid, mp 191-192 C (EtOAc) [lit5a mp 193-194 C]. IR (KBr) ν(cm-1): 2968, 2931, 2835,
15

ACCEPTED MANUSCRIPT
1612, 1325, 1252, 1032, 837. 1H NMR (400 MHz, CDCl3) δ: 8.74 (d, JH-H = 9.4 Hz, 1H), 7.97 (d, JH-H
=
7.9 Hz, 2H), 7.61 (d, JH-H = 8.5 Hz, 1H), 7.44 (d, JH-H = 8.6 Hz, 1H), 7.38 (d, JH-H = 9.4 Hz, 1H), 7.08 (s,
1H), 7.02 (d, JH-H = 7.8 Hz, 1H), 3.93 (s, 3H), 3.87 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 160.3, 159.0,
143.0, 137.7, 131.1 (CH), 130.6, 125.7, 124.5 (CH), 123.6 (CH), 122.4 (CH), 121.8 (CH), 113.6 (CH),
105.9 (CH), 55.6 (CH3), 55.3 (CH3). MS (ESI) m/z: 282.3 [M + H]+ (calcd for C17H16NO3+ 282.1).
4.2.20 2-(4-Methoxyphenyl)-8-methylquinoline 1-oxide (3u)
Yellow solid, mp 104-105 oC (EtOAc). IR (KBr) ν(cm-1): 3035, 2923, 1546, 1438, 1327, 864. 1H NMR
(400 MHz, CDCl3) δ: 8.76 (d, JH-H = 8.8 Hz, 2H), 7.60 (dd, JH-H = 7.0 Hz, JH-H = 0.7 Hz, 2H), 7.40-7.34
(m, 3H), 7.00 (d, JH-H = 8.8 Hz, 2H), 3.84 (s, 3H), 3.20 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 160.2,
146.0, 142.1, 134.0, 133.7 (CH), 131.3, 131.0 (CH), 127.6 (CH), 126.7 (CH), 126.3, 125.5 (CH),
122.9 (CH), 113.7 (CH), 55.3 (CH3), 25.6 (CH3). HR MS (ESI) m/z: 266.1175 [M + H]+ (calcd for
C17H16NO2+ 266.1176).
4.2.21 6-Chloro-2-(4-methoxyphenyl)quinoline 1-oxide (3v)
Yellow solid, mp 168-169 oC (EtOAc). IR (KBr) ν(cm-1): 2931, 1560, 1498, 1252, 1032, 810, 667. 1H
NMR (400 MHz, CDCl3) δ: 8.78 (d, JH-H = 9.3 Hz, 1H), 8.00 (d, JH-H = 8.6 Hz, 2H), 7.82 (s, 1H), 7.68 (d,
JH-H = 8.1 Hz, 1H), 7.63 (d, JH-H = 8.7 Hz, 1H), 7.54 (d, JH-H = 8.7 Hz, 1H), 7.03 (d, JH-H = 8.6 Hz, 2H),
3.88 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 160.6, 144.8, 140.8, 134.3, 131.2 (CH), 131.1 (CH),
129.9, 126.5 (CH), 125.1, 124.3 (CH), 124.1 (CH), 122.1 (CH), 113.7 (CH), 55.4 (CH3). HR MS (ESI)
m/z: 286.0632 [M + H]+ (calcd for C16H13ClNO2+ 286.0629).
4.2.22 6-Bromo-2-(4-methoxyphenyl)quinoline 1-oxide (3w)
Yellow solid, mp 182-183 oC (EtOAc) [lit7 mp 182-183 oC]. IR (KBr) ν(cm-1): 3128, 1609, 1520, 1405,
1
1215. H 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). MS (ESI) m/z:
330.1 [M + H]+ (calcd for C16H13BrNO2+ 330.0).
4.2.23 2-(4-Methoxyphenyl)-4-methylquinoline 1-oxide (3y)
o
o
Colorless solid, mp 73-74 C (EtOAc) [lit7 mp 73-74 C]. 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
16

ACCEPTED MANUSCRIPT
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). MS (ESI) m/z: 266.3
[M + H]+ (calcd for C17H16NO2+ 266.1).
4.2.24 3-bromo-2-(4-methoxyphenyl)quinoline 1-oxide (3z)
Yellow solid, mp 172-173 oC (EtOAc) [lit7 mp 172-173 oC]. 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). MS (ESI) m/z: 330.1 [M + H]+ (calcd for
C16H13BrNO2+ 330.0).
4.2.25 1-(4-Methoxyphenyl)isoquinoline 2-oxide (3az)
o
Yellow solid, mp 180-181 C (EtOAc). IR (KBr) ν(cm-1): 3041, 2927, 1520, 1323, 1228, 1176, 742,
663. 1H NMR (400 MHz, CDCl3) δ: 8.28 (d, JH-H = 7.2 Hz, 1H), 7.79 (d, JH-H = 7.5 Hz, 1H), 7.64 (d, JH-H
= 7.2 Hz, 1H), 7.55-7.48 (m, 5H), 7.11 (d, JH-H = 8.7 Hz, 2H), 3.90 (s, 3H). 13C NMR (100 MHz, CDCl3)
δ: 160.3, 146.02, 137.4 (CH), 131.7 (CH), 130.1, 129.7, 129.1, 128.9 (CH), 128.1 (CH), 126.8 (CH),
125.8 (CH), 123.0 (CH), 122.8, 114.2 (CH), 55.3 (CH3). HR MS (ESI) m/z: 252.1022 [M + H]+ (calcd
for C16H14NO2+ 252.1019).
4.3 The procedure for the Synthesis of 2-arylquinolines 5
In a 25 mL Schlenk tube, quinolines 4 (0.3 mmol), arylamines 2 (0.3 mmol), tert-butyl nitrite (0.36
mmol, 37.1 mg), and Cu(OAc)2 5H2O (0.045 mmol, 12.2 mg) as a catalyst in acetone/H2O (3.0 mL)
o
were added and the reaction was stirred at 50 C for 1.5 h (monitored by TLC). The reaction
mixture was diluted with ethyl acetate, and saturated sodium chloride solution washed three
times. The resulting organic phase was dried over anhydrous Na2SO4 and concentrated under
vacuum. The crude product was purified by silica gel column chromatography using ethyl
acetate/petroleum ether (1 : 4 to 1 : 10) as eluant to obtain the desired products 5.
4.3.1 2-(4-Ethylphenyl)-4-methylquinoline (5a)
Light yellow solid, mp 169-171 oC (from EtOAc). 1H NMR (400 MHz, CDCl3) δ: 8.19 (d, JH-H = 8.4 Hz,
1H), 8.05 (d, JH-H = 8.2 Hz, 2H), 7.99 (d, JH-H = 8.3 Hz, 1H), 7.73-7.69 (m, 2H), 7.53 (td, JH-H = 7.6 Hz,
JH-H = 1.0 Hz, 1H), 7.35 (d, JH-H = 8.2 Hz, 2H), 2.76-2.70 (m, 5H), 1.29 (t, JH-H = 7.6 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ: 157.2, 147.9, 145.6, 144.9, 137.0, 129.9 (CH), 129.4 (CH), 128.3 (CH), 127.5
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(CH), 127.1, 125.9 (CH), 123.5 (CH), 119.8 (CH), 28.6 (CH2), 18.9 (CH3), 15.4 (CH3). HR MS (ESI) m/z:
248.1438 [M + H]+ (calcd for C18H18N+ 248.1434).
4.3.2 2-(4-Methoxyphenyl)-4-methylquinoline (5b)
o
o
1
Light yellow solid, mp 110-111 C (from EtOAc; lib.20 110-112 C). H NMR (400 MHz, CDCl3) δ:
8.16-8.11 (m, 3H), 7.97 (d, JH-H = 8.3 Hz, 1H), 7.72-7.67 (m, 2H), 7.51 (td, JH-H = 7.6 Hz, JH-H = 1.0 Hz,
1H), 7.04 (d, JH-H = 8.8 Hz, 2H), 3.88 (s, 3H), 2.75 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 160.7, 156.6,
148.0, 144.6, 132.3, 130.0 (CH), 129.2 (CH), 128.8 (CH), 127.0, 125.6 (CH), 123.5 (CH), 119.3,
114.1 (CH), 55.4 (CH3), 19.0 (CH3). MS (ESI) m/z: 250.3 [M + H]+ (calcd for C17H16NO+ 250.1).
4.3.3 2-(2-Methoxyphenyl)-4-methylquinoline (5c)
Light yellow solid, mp 82-83 oC (from EtOAc; lib.21 83-84 oC). 1H NMR (400 MHz, CDCl3) δ: 8.18 (d,
JH-H = 8.4 Hz, 1H), 8.00 (d, JH-H = 8.2 Hz, 1H), 7.79 (dd, JH-H = 7.5 Hz, JH-H = 1.6 Hz, 1H), 7.71-7.68 (m,
2H), 7.55 (t, JH-H = 7.2 Hz, 1H), 7.41 (td, JH-H = 7.8 Hz, JH-H = 1.6 Hz, 1H), 7.11 (t, JH-H = 7.4 Hz, 1H),
7.03 (d, JH-H = 8.2 Hz, 1H), 3.86 (s, 3H), 2.74 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 1157.2, 156.8,
148.0, 143.2, 131.4 (CH), 130.2 (CH), 130.1 (CH), 128.9 (CH), 127.1, 125.9 (CH), 124.0 (CH), 123.5
(CH), 121.2 (CH), 111.4 (CH), 55.7 (CH3), 18.9 (CH3). MS (ESI) m/z: 250.2 [M + H]+ (calcd for
C17H16NO+ 250.1).
4.3.4 2-(p-Tolyl)quinoline (5d)
Light yellow solid, mp 81-82 oC (from EtOAc; lib.22 82-84 oC). 1H NMR (400 MHz, CDCl3) δ: 8.18 (d,
JH-H = 8.5 Hz, 2H), 8.08 (d, JH-H = 8.2 Hz, 2H), 7.85 (d, JH-H = 8.6 Hz, 1H), 7.81 (dd, JH-H = 8.2 Hz, JH-H
=
0.9 Hz, 1H), 7.72 (td, JH-H = 6.8 Hz, JH-H = 1.2 Hz, 1H), 7.51 (td, JH-H = 7.8 Hz, JH-H = 0.7 Hz, 1H), 7.34
(d, JH-H = 8.0 Hz, 2H), 2.44 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 157.3, 148.3, 139.4, 136.8, 136.6
(CH), 129.6 (CH), 129.5 (CH), 127.4 (CH), 127.1, 126.1 (CH), 118.8 (CH), 21.3 (CH3). IR (KBr) ν(cm-1):
2956, 1597, 1556, 1496. MS (ESI) m/z: 220.3 [M + H]+ (calcd for C16H14N+ 220.1).
4.3.5 4-(p-Tolyl)quinoline (5d′)
Light yellow solid, mp 88-89 oC (from EtOAc; lib.23 90.5-91.5 oC ). 1H NMR (400 MHz, CDCl3) δ: 8.93
(d, JH-H = 4.4 Hz, 1H), 8.17 (d, JH-H = 8.4 Hz, 1H), 7.95 (d, JH-H = 7.7 Hz, 1H), 7.72 (td, JH-H = 8.2 Hz,
JH-H = 2.4 Hz, 1H), 7.51-7.47 (m, 1H), 7.40 (d, JH-H = 7.2 Hz, 2H), 7.34-7.31 (m, 3H), 2.46 (s, 3H). 13
C
NMR (100 MHz, CDCl3) δ: 149.9 (CH), 148.6, 138.3, 135.0, 129.9, 129.8 (CH), 129.4 (CH), 129.2
(CH), 129.1, 126.9, 126.5 (CH), 125.9 (CH), 121.3 (CH), 21.3 (CH3). IR (KBr) ν(cm-1): 2956, 1614,
1585, 1502. MS (ESI) m/z: 220.2 [M + H]+ (calcd for C16H14N+ 220.1).
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Acknowledgement
This work was supported by the 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), and Project of Youth Backbone Teachers of Henan University of Technology.
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