DMSO/t-BuONa/O2-Mediated Aerobic Dehydrogenation of Saturated N-Heterocycles

Article abstract of DOI:10.1021/acs.joc.9b03447

Aromatic N-heterocycles such as quinolines, isoquinolines, and indolines are synthesized via sodium tert-butoxide-promoted oxidative dehydrogenation of the saturated heterocycles in DMSO solution. This reaction proceeds under mild reaction conditions and has a good functional group tolerance. Mechanistic studies suggest a radical pathway involving hydrogen abstraction of dimsyl radicals from the N-H bond or α-C-H of the substrates and subsequent oxidation of the nitrogen or α-aminoalkyl radicals.

Full text of DOI:10.1021/acs.joc.9b03447

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Note
DMSO/t-BuONa/O2 mediated Aerobic
Dehydrogenation of Saturated N-Heterocycles
Ruchun Yang, Shusheng Yue, Wei Tan, Yongfa Xie, and Hu Cai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03447 • Publication Date (Web): 05 May 2020
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DMSO/t-BuONa/O mediated Aerobic Dehydrogenation
2
of Saturated N-Heterocycles
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a, b
a
c
a
a
Ruchun Yang , Shusheng Yue , Wei Tan , Yongfa Xie* and Hu Cai*
a
College of Chemistry, Nanchang University, Nanchang 330031, China. E-mail:
caihu@ncu.edu.cn，xieyf@ncu.edu.cn
b
Institute of Organic Chemistry, Jiangxi Science & Technology Normal University, Key
Laboratory of Organic Chemistry, Jiangxi Province, Nanchang 330013
c
Clinic Laboratory, People’s Hospital of Yichun City, Jiangxi Province, Yichun 336000
ABSTRACT:
NH
N
R
R2
R
N
R2
R2
t-BuONa(3eq)
R1
R1
R1
DMSO, O2, 4h
N
N
H
R2
Possible transition state
R2
R1
R1
N
N
H
H
Metal-free
3
0 Examples
Mild Conditions
Yields up to 85%
Aromatic N-Heterocycles such as quinolines, isoquinolines and indolines are synthesized
via a sodium tert-butoxide promoted oxidative dehydrogenation of the saturated
heterocycles in DMSO solution. This reaction proceeds under mild reaction conditions
and has a good functional group tolerance. Mechanistic studies suggest a radical pathway
involving hydrogen abstraction of dimsyl radicals from the N-H bond or α-C-H of the
substrates, and subsequent oxidation of the nitrogen or α-aminoalkyl radicals.
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Dehydrogenation of saturated and partially saturated heterocycles is an efficient and
atom-economic synthetic route for functionalized heterocyclic compounds with the
advantage of avoiding the usually tedious multi-step procedures for regioselective
introducing varied substituents at the preformed heterocycles. The dehydrogenation can
be achieved either oxidatively with the help of a hydrogen acceptor (oxidative
dehydrogenation, ODH),1,2 or in an process with the evolution of hydrogen gas
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(
acceptorless dehydrogenation, ADH). Traditional ODH protocols use stoichiometric
amount of DDQ, o-Iodoxybenzoic acid (IBX), KMnO , metal oxide, etc. as oxidants and
4
is not environmentally friendly by leaving a large amount of reduced oxidants as wastes.
2
In contrary, the catalytic ODH reaction proceeds with molecular oxygen as the hydrogen
acceptor and water as the only by-product.
4
Quinolines are ubiquitous structural motifs found in many natural products and
5
pharmaceuticals . The synthesis of diverse functionalized quinolines by the
dehydrogenation of tetrahydroquinolines (THQ) has drawn much research interest in
recent years. Catalytic ODH reactions of THQ have been realized by using metal
6
complexes based on precious metals Ir, Ru, Rh, Pd and non-precious metals Fe, Co, Ni,
Cu, V, etc.,7,8 and by using graphene oxide as catalyst. Several metal co-catalyzed,
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redox-active compounds (o-quinones, azadicarboxylates, TEMPO) mediated ODH
1
0
11
reactions and photoredox catalyzed ODH reactions have also been reported. At the
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meantime, many ADH reactions of THQ have been developed using complexes of
transition metals12 ,13 (Ir, Ru, Co, Ni, Fe etc.), borane14 or frustrated Lewis pair15 as
catalyst. Photoredox16 and electrolytic17 catalysis has also proved to be effective in
carrying out ADH reactions. All these ODH and ADH reactions provided complementary
approaches for the access of functionalized quinolines from THQ, but have their own
respective limitations and shortcomings, such as the high cost of the metal complexes and
the ligands, harsh reaction conditions of high reaction temperature or long reaction times,
and limited tolerance to a wide range of functional groups. Therefore, it is highly
important to further pursue new efficient dehydrogenation protocols of THQ with good
functional group tolerance and proceeding under mild reaction conditions.
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Strong bases such as potassium tert-butoxide and potassium hydroxide have shown
great potential in metal-free C-C coupling of unreactive arenes with aryl halides18,19 since
Itami19a and his co-workers unexpectedly found in 2008 a coupling reaction of
iodobenzene with pyrazine, only promoted by stoichiometric amount of t-BuOK(scheme
1
a). Strong bases have also been found to be effective in N-H bond activation for C-N
bond formation in addition reactions of amines to alkynes and olefins (scheme 1b).20
3
Construction of C-C bond through cross dehydrogenative coupling reaction of sp C-H or
2
sp C-H with nitrobenzene in the t-BuOK/DMSO/air system was reported as well(scheme
1
c).21 Very recently, a potassium tert-butoxide promoted ADH reaction of THQ was
2
2
reported that proceeded in o-xylene solution at 140 C (Scheme 1d). We herein report a
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sodium tert-butoxide promoted dehydrogenation reaction of THQ, that, however, is
different from the previously reported t-BuOK promoted reaction by proceeding via an
ODH pathway under milder reaction conditions with tolerance of a diversity of functional
groups.
0
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0
I
OMe
N
N
t-BuOK(1.5eq)
N
(a)
5
0oC, 5min
MW
83%
N
OMe
H2N
H2N
KOH(0.5eq)
(b)
o
DMSO, 120 C
N
N
H
R
R
72%
NO2
Ar(NO2)
t-BuOK(2eq)
(
c) X/R
DMSO, air X/R
N
H
46-77%
R/X
N
H
Me
Me
N
t-BuOK(3eq)
(
d)
o
o-xylene, N2, 140 C, 36h
N
H
85%
T his work
Ph
Ph
t-BuONa(3eq)
o
DMSO, 1atm O2, 60 C, 4h
85%
N
H
N
Scheme 1: Base-promoted dehydrogenative C-C and C-N bond formation reactions
For our initial studies, 1, 2, 3, 4- tetrahydroquinoline(1a) was chosen as a substrate
in a base/DMSO/O
revealed that both oxygen and base are required for this reaction. Under the atmosphere
of argon, the desired oxidative reaction did not proceed. Various bases such as Cs CO
KOH, CH ONa, NaH, t-BuOLi, t-BuOK and t-BuONa were screened for the optimization
2
system (Table 1). Control experiments (Table 1, entries 8-10)
2
3
,
3
of reaction conditions (Table 1, entries 1-7). It was found that t-BuONa was the best base
for promoting the dehydrogenation reactions. And stoichiometric base was needed for
this reaction, while catalytic amount of base cannot lead to a complete conversion of the
substrate (Table1, entry 11 and 12).
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Table 1: Optimization of Reaction Conditionsa
base
solvent
N
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
a
1
2a
entry
base
Cs
solvent
T
yieldb
1
2
2
CO
3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DCM
4h
4h
trace
11
KOH
t-BuOLi
CH ONa
3
4h
8
4
3
4h
16
5
t-BuONa
t-BuOK
NaH
4h
65
6
4h
61
7
4h
23
8c
9d
t-BuONa
t-BuONa
--
12h
12h
12h
12h
12h
12h
12h
12h
12h
12h
12h
16
n.r.
n.r.
5
10
1e
1
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
2f
1
52
1
3
4
n.r.
n.r.
32
1
Toluene
DMF
15
16
CH
CH
DMSO
3
OH
n.r.
n.r.
53
17
18g
3
CN
aUnless otherwise noted, all reactions were performed
with 0.6 mmol 1a, 3eq t-BuONa, in 2.0 mL DMSO at 60

C under 1 atm O
2
, 4h; b) isolated yields; c) open air
atmosphere; d) Reaction performed under an argon
atmosphere; e) 0.2eq t-BuONa; f) 2.2eq t-BuONa; g)
Reaction performed under 120 C.
Other solvents such as DMF, DCM, CH
3
CN, CH OH and toluene were also
3
examined in the reaction (Table1, entries 13-18). Unfortunately, none of these solvents
gave the product 2a except DMF (Table 1, entry 16) giving 32% yield. Furthermore, no
improvements were observed when the reaction was carried out by increasing reaction
time and elevating reaction temperature (Table 1, entry 19). After extensive screening of
various conditions, the best reaction conditions are set at carrying out the reaction with 3
equivalents of t-BuONa at 60 C under 1 atm of oxygen (Table 1, entry5).
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
4
4
4
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4
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4
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Under the optimized conditions, various substituted quinolines were generated from
the corresponding THQ by this new method. The results in Table 2 confirmed that a
broad range of substitution patterns on the tetrahydroquinoline were tolerated and the
products were obtained in moderate to good yields. It is noteworthy that
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
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0
4
-phenyl-1,2,3,4-tetrahydroquinoline derivatives performed much well, giving the
product 2f-2q in 58%-85% yields, and 4-phenyl-1,2,3,4-tetrahydroquinoline exhibited the
highest efficiency affording the desired 2f in 85% yield. Besides, the compounds
containing methyl group (1b, 1c, 1n, 1p, respectively) gave lower yields. Fortunately,
tetrahydroquinoline with strong electron-withdrawing group(-CF ) also resulted in the
3
desired product (2r, 11%).
Table 2: Metal-free Aerobic Oxidation of 1,2,3,4-Tetrahydroquinoline to Quinolinea
R
R
t-BuONa(3eq)
R
R
DMSO,60°C
O2 (1atm),4h
N
N
H
1
2
1
2
Cl
2a, R , R =H,65%
1
2
2
2
b, R = 6-CH3, R =H,55%
R1
R2
1
2
c, R = H, R =2-CH3, 47%
N
N
2d
1
2
2e, 46%
,
R = 6-OCH3, R =H, 56%
Cl
3
2k, R3=6-F, 69%
2l, R3=6-Cl, 75%
Ph
2f, R =H,85%
2
3
g, R =8-OCH3,78%
3
2m
, R =6-OCH3, 65%
3
R3
2h, R =8-CH3, 67%
3
2n, R3=6-CH , 45%
2
2
i, R =8-Cl, 62%
3
N
3
2o, R3=6-Br, 58%
j, R =8-Br,63%
R4
Ph
Ph
F3C
N
N
N
4
R =p-fluorophenyl
2q, 63%
2
pb, 53%
2r,
11%
a)
Reaction conditions: 0.2-0.6 mmol 1a-1r, 3eq t-BuONa, in 2.0
, 4h; b) Room temperature.
mL DMSO at 60 C under 1 atm O
2
Table 3: Dehydrogenation of other N-heterocyclic Derivatives
R
R
N
t-BuONa(3eq)
R
R
or
R
DMSO
NH
N
O2 (1atm),4h
H
3a-3l
4a-4l
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R1
1
4
4
4
4
a, R =H, 35%
R2
1
2
b, R =Br, 56%
4e, R =F, 58%
1
2
c, R =CH3, 61%
4f,
R
=Br, 41%
N
N
1
d, R =Cl, 63%
H
H
CH3
N
N
N
4
h, 63% O2N
4i, 73%
4l, 65%
H
4g, 15%
H
H
CN
N
N
b
N
4j, 71%
4k , 10%
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
Ph
a) Reaction conditions: 0.4-0.6 mmol 3a-3l, 3eq t-BuONa, in 2.0
mL DMSO under 1 atm O , 4h, 60 C; b) 12h, 120 C.
2
The above strategy was further applied for the synthesis of other N-heteroarene
derivatives and the results are listed in Table 3. Treatment of indoline substrates under the
standard conditions gave the products in 35-73% yields(Table 3, 4a-4j). The results in
Table 3 confirmed that a broad range of substitution patterns(CH
3
, Br, Cl, F, NO , CN
2
etc.) on the indoline were tolerated and the products were obtained in moderate yields. It
is noteworthy that substrates with electron-withdrawing group(4h-4j) performed relative
high yields. Under the reaction conditions, treatment of 1,2,3,4-tetrahydroisoquinoline
yielded the product 4k in 10% with most of the starting material remained. There was a
dramatic increase in the yield when 1-phenyl-tetraisoquinoline 3l was used as a substrate
(Table 3, 4l). From the above results, we can conclude that this mild condition oxidative
dehydrogenation method has a large substrate scope. Substrates of N-heterocycles such as
tetrahydroquinolines,
indolines,
and
tetrahydroisoquinolines
with
either
electro-withdrawing or electro-donating substituents worked well.
To gain insight into the reaction mechanism, we tested the effect of the free radical
scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) on the reaction and found that
the addition of two equivalents of TEMPO to the reaction mixture resulted in a drastic
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2
2
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inhibiting of the oxidation reaction, and only 9% yield of desired product was obtained
(Scheme 2a). This result suggests that a radical intermediate may be involved during the
transforming.
0
1
2
3
4
5
6
7
8
9
0
1
2
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0
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2
3
4
5
6
7
8
9
0
To get further evidence of the reaction mechanism, DMSO-d
6
was used as the
solvent alternating the non-deuterated DMSO in the standard reaction (Scheme 2a). Then
1
1
the reaction mixture was monitored at regular time interval by H NMR. In the H
NMR(SI, Figure 1s(a)), the starting material(1a) was consumed and the product(2a)
increase gradually. Significantly, the enlargement of integral peak area at δ=2.91ppm as
the reaction time increases indicates the increasing amount of CD
during the reaction (SI, Figure 1s(a)). CD SO CD H was also confirmed by
GC-MS(Retention time = 5.28 min, m/z: 99.0) of the reaction after 4 hours stirring(SI,
Figure 3s). A proton exchanged DMSO-d , CD SOCD H was produced during the
reaction as well(SI, Scheme 1s). Since intense quintet peaks at δ=39.6 ppm were
observed by DEPT-135 NMR due to the C-D coupling of -CD H group, while -CD
group could not exhibited in DEPT-135 NMR spectrum(SI, Figure 2s(c)). The produced
CD SOCD H was also confirmed by GC-MS results(SI, Figure 3s, Retention time = 4.73
3
SO
2
CD
2
H produced
3
2
2
6
3
2
2
3
3
2
min, m/z: 83.0). In addition, a broad peak shifted from 4.4 ppm to 3.57 ppm in regular
1
time interval H NMR due to the variation of concentration or pH value of the reaction
system(SI, Figure 1s(b)). We propose that the broad peak is water produced during the
reaction. To verify this hypothesis, after 4h stirring, 5 l H O was added to the NMR tube
2
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and measured H NMR of the mixture again. The integral area at δ3.57 ppm increased
and the chemical shift coincided with that of the mixture before adding water (SI, Figure
1
s). According to the results of these spectra, we propose that DMSO-d
6
was oxidized
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
into DMSO -d by hydrogen peroxide, resulted in water molecules.
2
6
Furthermore，to verify whether the NH moiety in the substrate is a necessitate for the
dehydrogenation, reactions of substrates 1u, 1v, 1w and 1x were carried out under the
standard conditions respectively. No reactions were found for substrates 1u and 1v
(
scheme 2b). When diphenylmethane (1w) was the substrate, benzophenone was isolated
in 83% yield (scheme 2c). For the N-methyl tetrahydroquinoline 1x, 2x′ was isolated in
8% yield and the dehydrogenated product was not observed (Scheme 2d). These facts
7
reveal that N-H is essential in the reaction and the dehydrogenation is probably initiated
by the deprotonation of the N-H bond leading to a nitrogen radical rather than
deprotonation at the benzyl C-H bond in the first step.
H
2
eq tempo
3eq t-BuONa
H
byproduct
3eq t-BuONa
(
a)
DMSO-d5
DMSO2
DMSO,O2
DMSO-d6,O2
60°C, 4h
N
N
N
H
60°C,4h
H
2
a
2a, 9%
1a
3eq t-BuONa
(
b)
or
DMSO-d6,O2
no reaction
N
60°C, 12h
1
u
1v
eq t-BuONa
O
3
(c)
DMSO-d6,O2
1w
60°C, 4h
2
w', 83%
Ph
Ph
Ph
OH
(d)
3eq t-BuONa
N
N
DMSO-d ,O2
N
6
CH3
not observed
CH3
60°C, 4h
CH3 2x', 78%
1x
Scheme 2: Control Experiments
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2
2
2
2
2
2
3
3
3
3
3
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3
3
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3
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
6
Additionally, EPR measurement shows that after mixing 1,2,3,4-tetrahydroquinoline
and t-BuONa in DMSO at 1 atmosphere pressure of oxygen at room temperature, a
radical signal was observed in situ (Figure 1). This EPR signal represents probably a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
nitrogen radical with a g-value of 2.0050 (A = 11.5 G). Under the same conditions,
N
when either 1,2,3,4-tetrahydroquinoline or t-BuONa was absent, no EPR signal was
detected (see SI, Figure 4s).
g-value
2.03
2.02
2.01
2.00
1.99
1.98
0
.20
.15
A =11.2 G
N
0
g=2.0050
0.10
0
.05
.00
0
3480
3500
3520
Magnetic field (G)
3540
3560
Figure 1: EPR spectrum of mixture of t-BuONa and 1,2,3,4-tetrahydroquinoline in
DMSO solution at room temperature under 1 atm O
2
.
Based on the above experimental results, two proposed mechanism pathways for the
conversion of the tetrahydroquinoline (THQ) 1a to quinoline 2a are presented in Scheme
3
. DMSO has a pK
a
of 35 and tert-butanol as the conjugate acid of t-BuOK has a pK of
a
2
3
32.2 in DMSO solution. As a consequence, DMSO can be partly deprotonated by
2
4
sodium tert-butoxide to give dimsyl carbanions. The dimsyl anions have been proposed
to serve as electron donors in thermal single electron transfer (SET) reactions with such
electron acceptors as iodobenzene25 (half-wave reduction potential 1.81 V, SCE26),
therefore, they may be oxidized by the molecular oxygen (half-wave reduction potential
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0.75 V, SCE) to give dimsyl radicals. This kind of mechanism was also proposed by
Haland 28 and Hawkins with their coauthors. The dismyl radical may act as a hydrogen
29
30
atom abstractor from THQ at the N-H bond which has a rather low dissociation energy
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
of～85.9 kcal/mol31,32 to lead the 1-tetrahydroquinolinyl radical A, or from THQ at the
33
α-C-H bond leading to the C-centered radical B. A may combine with oxygen to lead to
the peroxy radical D, which also give dihydroquinoline by first abstracting a H atom from
THQ to give the hydroperoxide E and subsequent elimination of hydrogen peroxide.
Alternatively, As an aminoalkyl radical, B has a low oxidation potential of ～1.12 V
3
3
(SCE), which undergoes exothermic SET oxidation by oxygen to afford the carbocation
C, which upon deprotonation give the 3,4-dihydroquinoline as a primary product.
Isomerization of the 3,4-dihydroquinoline to the 1,2-dihydroquinoline7b,11b,11c,13b and
subsequent oxidative dehydrogenation of the later following the same reaction sequence
described above finally render the quinoline product.
O2
N
N
H
H+
H
-
O
S
C
B
H3C
CH2
path a
O2
B:
N
N
O
S
2a1
O
2
a
S
H3C
CH2
-H2O2
H3C
CH3
H2O2
N
a
H
1
DMSO2 H2O
path b
N
E
O
HO
1a
N
N
O2
A
D
O
O
Scheme 3: Proposed Reaction Mechanism
In summary, we have developed a metal-free protocol for oxidative
dehydrogenation of 1,2,3,4-tetrahydroquinolines in the t-BuONa/DMSO/O system.
2
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2
2
2
2
2
2
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4
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5
6
This dehydrogenation proceeds under mild reaction conditions and has good
functional group tolerance. Mechanistic studies including spin trap and isotope
labeling experiments indicated a radical pathway, which was initiated by hydrogen
abstraction from the N-H bond of the substrates by the dimsyl radicals derived
from SET oxidation of the dimsyl anion. Further extension of the reaction scope to
other N-heterocycles using this system and further mechanistic studies are
currently under way.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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5
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7
8
9
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1
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8
9
0
EXPERIMENTAL SECTION
General Remarks:
All commercially available substrates were used as received. DMSO was dried over CaH
2
,
distilled under reduced pressure, and stored under an argon atmosphere over activated 4
1
13
Å molecular sieves in Teflon screwed Schlenk flasks before using. H and C NMR
spectra were recorded on Bruker 400 MHz spectrometers and chemical shifts are given in
1
parts per million (ppm) relative to standard tetramethylsilane (0.00 ppm for H NMR) or
residual solvent peaks for 13 C NMR. HR-MS was obtained using a Q-TOF instrument
equipped with ESI source. GC-MS results were obtained by the Agilent 7000C GC/MSD
system equipped with the HP-5MS (30m, 0.25mm, 0.25μm) column. The ESR Spectra
were recorded on a Bruker E500 spectrometer at 20 C. Standard column
chromatography was performed on 200-300 mesh silica gel. using flash column
chromatography techniques.
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General Procedure for the Preparation of Quinoline and other N-heterocycles
To a disposable 13 mm
substrates 1a-1r and 3a-3l (0.2-0.6 mmol), then dry DMSO (2 mL) was added to the
mixture. The test tube was vacuumed，and purged for 5 minutes with O . The headspace
was then filled with O at a pressure of 1 atm. The mixture was allowed to stirred at 60
C in oil bath for 4-18 h. After the stirring was stopped, the mixture was allowed to cool
to room temperature. O pressure was released and the resulting brown solution was
washed with water and then extracted with CH Cl . The combined organic layers were
dried over Na SO , and filtered through a short pad of celite. The filtrate was evaporated
100 mm thick-walled tube were added sequentially t-BuONa and
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
2
2
2
2
4
in vacuum, and the residue was purified by column chromatography.
Gram scale reaction for the Preparation of Quinoline
To a round-bottomed flask (100mL) were added sequentially t-BuONa (2.16 g, 22.6
mmol) and substrates 1a (1.00g, 7.52mmol), then dry DMSO (25 mL) was added to the
mixture. The flask was vacuumed，and purged with O . Repeat this three times. The
2
mixture was allowed to stirred at 60 C in oil bath for 4h. After the stirring was stopped,
the mixture was allowed to cool to room temperature. The resulting brown solution was
washed with water and then extracted with CH
dried over Na SO , and filtered through a short pad of celite. The resultant residue was
purified by flash column chromatography on silica gel (eluent: petroleum ether /EtOAc =
00:1-40:1, v/v) to afford 2a as a yellow oil (504.7 mg, yield 52%) and the by-product 2a
as a white solid (55.3 mg, yield 5%).
2
Cl
2
. The combined organic layers were
2
4
1
′
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6
Characterization Data for Isolated Products
Quinoline
00:1-40:1, v/v) ; 1H NMR (400 MHz, CDCl
2H), 7.79 (d, J = 8 Hz, 1H), 7.71 (m, 1H), 7.53 (t, J = 8 Hz, 1H), 7.34 (m, 1H).
(
2a).10e Yellow oil (50.3 mg, yield 65%,; eluent: petroleum ether /EtOAc =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
) δ 8.91(dd, J = 8Hz, 1H), 8.11 (m,
13C{H}
NMR (100 MHz, CDCl
) δ 150.4, 148.2, 136.0, 129.42, 128.2, 127.7,
3
+
126.4, 121.0. HRMS (ESI, m/z): Calcd. for C
9
H
7
N: [M+H] = 130.0651; found:
1
30.0654.
,4-dihydroquinolin-2(1H)-one (byproduct 2a′).34 White solid (55.3 mg, yield 5%;
) δ 9.47
(s, 1H), 7.17 (d, J = 7.4 Hz, 2H), 6.99 (t, J = 7.0 Hz, 1H), 6.88 (d, J = 7.4 Hz, 1H),
.98 (t, J = 6.8 Hz, 2H), 2.66 (t, J = 7.0 Hz, 2H). 13C{H} NMR (100 MHz, CDCl
3
eluent: petroleum ether /EtOAc = 10:1-1:1, v/v) ; 1H NMR (400 MHz, CDCl
3
2
3
)
δ 172.4, 137.3, 127.8, 127.5, 123.6, 123.0, 115.6, 30.7, 25.3. HRMS (ESI, m/z):
+
Calcd. for C
9
H
9
NO: [M+H] = 147.0684; found: 147.0686.
6-methylquinoline(2b).10e Yellow oil (47.2 mg, yield 55%; eluent: petroleum ether
EtOAc = 100:1-40:1, v/v); 1H NMR (400 MHz, CDCl
) δ 8.81(m, 1H), 8.00 (m,
2H), 7.49 (m, 2H), 7.30 (dd, J = 8.2, 4.2 Hz, 1H), 2.49 (s, 3H). 13C{H} NMR (100
/
3
MHz, CDCl
3
) δ 149.4, 146.8, 136.4, 135.4, 131.7, 129.0, 128.3, 126.6, 121.0, 21.5.
+
HRMS (ESI, m/z): Calcd. for C10
H
9
N: [M+H] = 144.0807; found: 144.0811.
2
-methylquinolin(2c).10e Yellow oil (40.3 mg, yield 47%; eluent: petroleum ether
/EtOAc = 100:1-40:1, v/v); 1H NMR (400 MHz, CDCl
) δ 8.02 (d, J = 8.4 Hz, 1H),
3
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7.76 (d, J = 8.1 Hz, 1H), 7.67 (t, J = 7.6, Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.27 (t,
J =8.4 Hz, 1H), 2.74 (s, 3H). 13C{H} NMR (100 MHz, CDCl
) δ 158.9, 147.8,
3
1
36.1, 129.4, 128.6, 127.4, 126.4, 125.6, 122.0, 25.4. HRMS (ESI, m/z): Calcd.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
for C10
H N: [M+H] = 144.0807; found: 144.0809.
9
6-methoxyquinoline(2d).10a White solid (53.4 mg, yield 56%; eluent: petroleum ether
EtOAc = 100:1-40:1, v/v); 1H NMR (400 MHz, CDCl
) δ 8.67 (d, J = 4.2 Hz, 1H),
.93 (t, J = 9.2 Hz, 2H), 7.34-7.21 (m, 2H), 6.96 (s, 1H), 3.82 (s, 3H). 13C{H}
/
3
7
NMR (100 MHz, CDCl
3
) δ 157.7, 147.9, 144.3, 134.8, 130.8, 129.3, 122.3, 121.3,
+
1
05.1, 55.5. HRMS (ESI, m/z): Calcd. for C10
160.0759.
6,8-dichloroquinoline(2e).35 White solid (27.2 mg, yield 46%; eluent: petroleum ether
EtOAc = 100:1-40:1, v/v); 1H NMR (400 MHz, CDCl
) δ 9.05 (dd, J = 4.2, 1.2 Hz,
H), 8.13 (dd, J = 8.4, 1.2 Hz, 1H), 7.86 (d, J = 2.1 Hz, 1H), 7.77 (d, J = 2.0 Hz,
1H), 7.52 (dd, J = 8.4, 4.2 Hz, 1H). 13C{H} NMR (100 MHz, CDCl
) δ 151.1,
43.1, 135.7, 134.8, 131.8, 130.3, 129.7, 125.7, 122.8. HRMS (ESI, m/z): Calcd.
H
9
NO: [M+H] = 160.0757; found:
/
3
1
3
1
+
for C
9
H
5
Cl N: [M+H] = 197.9877; found: 197.9875.
2
4
-phenylquinoline(2f). 10e White solid (69.7 mg, yield 85%; eluent: petroleum ether
EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
) δ 8.94 (s, 1H), 8.20 (d, J =
.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.71 (t, J = 7.4 Hz, 1H), 7.55-7.43 (m, 6H),
/
3
8
7.31 (d, J = 4.2 Hz, 1H). 13C{H} NMR (100 MHz, CDCl
) δ 149.8, 148.7, 148.6,
3
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1
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1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
5
6
138.0, 129.8, 129.5, 129.3, 128.5, 128.4, 126.8, 126.6, 125.9, 121.3. HRMS (ESI,
+
m/z): Calcd. for C15
H
11N: [M+H] = 206.0969; found: 206.0964.
8
-methoxy-4-phenylquinoline(2g).36 White solid (73.3 mg, yield 78%; eluent:
petroleum ether /EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
) δ 8.98 (d, J =
4.4 Hz, 1H), 7.55-7.37 (m, 8H), 7.09 (d, J = 7.6 Hz, 1H), 4.12 (s, 3H). 13C{H}
NMR (100 MHz, CDCl ) δ 156.8, 150.5, 149.7, 141.4, 139.6, 130.9, 129.9 2,
29.4, 128.2, 123.4, 119.1, 109.1, 57.6. HRMS (ESI, m/z): Calcd. for C16
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3

1
H13NO:
+
[
M+H] = 236.1075; found: 236.1071.
8-methyl-4-phenylquinoline(2h).10e White solid (58.7 mg, yield 67%; eluent:
petroleum ether /EtOAc = 40:1-10:1, v/v) ; 1H NMR (400 2MHz, CDCl
) δ 8.88 (d, J
= 4.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 7.0 Hz, 1H), 7.45-7.35 (m,
3
5
H), 7.33-7.20 (m, 2H), 2.78 (s, 3H). 13C{H} NMR (100 MHz, CDCl
3
) δ 148.8,
1
48.7, 147.7, 138.5, 137.3, 129.6 2, 128.5, 128.3, 126.8, 126.3, 124.0, 121.2, 18.7.

+
HRMS (ESI, m/z): Calcd. for C16
8-chloro-4-phenylquinoline(2i).37 White solid (59.3 mg, yield 62%; eluent: petroleum
ether /EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
) δ 8.98 (d, J = 3.9 Hz,
H), 7.75 (d, J = 8.2 Hz, 2H), 7.40-7.31 (m, 7H). 13C{H} NMR (100 MHz, CDCl
H
3
N: [M+H] = 220.1126; found: 220.1129.
3
1
3
)
δ 150.3, 149.2, 144.8, 137.5, 133.8, 129.5, 129.4, 128.7, 128.6, 128.2, 126.3, 125.1,
+
122.1. HRMS (ESI, m/z): Calcd. for C15
H
10ClN: [M+H] =240.0580; found:
240.0574.
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8-bromo-4-phenylquinoline(2j).37 White solid (71.3 mg, yield 63%; eluent:
petroleum ether /EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
) δ 8.99 (d, J =
3
7.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.39-7.48 (m, 5H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7.31 (d, J = 4.4 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H). 13C{H} NMR (100 MHz, CDCl
)
3
δ 150.7, 149.2, 145.7, 137.6, 133.2, 129.5, 128.7

2, 128.3, 126.9, 126.0, 125.3,
122.2. HRMS (ESI, m/z): Calcd. for C15
H
10BrN: [M+H]+ =284.0075;
found:284.0079.
6
-fluoro-4-phenylquinoline(2k).37 White solid (61.5 mg, yield 69%; eluent:
petroleum ether /EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
) δ 8.80 (d, J =
4.4 Hz, 1H), 8.07 (dd, J = 9.2, 5.6 Hz, 1H), 7.47-7.34 (m, 7H), 7.24 (d, J = 4.4 Hz,
H). 13C{H} NMR (100 MHz, CDCl
) δ 160.7 (d, J = 246 Hz), 149.2 2, 148.1 (d,
J = 5.6 Hz), 145.7, 132.3 (d, J = 9.1 Hz), 129.3, 128.8, 128.7, 127.6 (d, J = 9.7 Hz),
3
1
3

121.8, 119.6(d, J = 25.7 Hz), 109.2(d, J = 22.9 Hz). HRMS (ESI, m/z): Calcd. for
+
C
15
H
10FN: [M+H] = 224.0875; found: 224.0869.
6
-chloro-4-phenylquinoline(2l).37 White solid (71.7 mg, yield 69%; eluent: petroleum
ether /EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
) δ 8.84 (d, J = 4.4 Hz,
H), 8.04 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 9.0, 2.2 Hz,
H), 7.50-7.36 (m, 5H), 7.27 (d, J = 4.4 Hz, 1H). 13C{H} NMR (100 MHz, CDCl
3
1
1
3
)
δ 150.0, 147.9, 146.9, 137.2, 132.7, 131.3, 130.3, 129.4, 128.8, 128.7, 127.5, 124.7,
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
122.0. HRMS (ESI, m/z): Calcd. for C15H10ClN: [M+H] = 240.0580; found:
2
40.0579.
-methoxy-4-phenylquinoline(2m).38 White solid (61.1 mg, yield 69%; eluent:
) δ 8.80 (d, J =
4.4 Hz, 1H), 8.08 (d, J = 9.2 Hz, 1H), 7.57-7.46 (m, 5H), 7.39 (dd, J = 9.2, 2.6 Hz,
H), 7.28 (d, J = 4.4 Hz, 1H), 7.19 (d, J = 2.6 Hz, 1H), 3.79 (s, 3H). 13C{H} NMR
100 MHz, CDCl ) δ 157.9, 147.6, 147.1, 144.9, 138.4, 131.3, 129.3, 128.7, 128.4,
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
petroleum ether /EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
3
1
(
3
1
27.7, 121.8, 121.7, 103.7, 55.5. HRMS (ESI, m/z): Calcd. for C16H13NO:
+
[
M+H] = 236.1075; found:236.1072.
6
-methyl-4-phenylquinoline(2n).10e White solid (40.3 mg, yield 46%; eluent:
) δ 8.76 (d, J =
.4 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.57 (s, 1H), 7.48-7.36 (m, 6H), 7.18 (d, J =
.4 Hz, 1H), 2.36 (s, 3H). 13C{H} NMR (100 MHz, CDCl
) δ 148.9, 148.0, 147.1,
petroleum ether /EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
3
4
4
3
138.2, 136.7, 131.7, 129.5, 129.4, 128.6, 128.4, 126.7, 124.6, 121.4, 21.8. HRMS
+
(
ESI, m/z): Calcd. for C16
H
3
N: [M+H] = 220.1126; found: 220.1125.
6
-bromo-4-phenylquinoline (2o).38 White solid (49.2 mg, yield 58%; eluent:
petroleum ether /EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
) δ 8.95 (d, J =
.3 Hz, 1H), 8.05 (d, J = 9.4 Hz, 2H), 7.80 (d, J = 9.0 Hz, 1H), 7.56-7.48 (m, 5H),
3
4
7
.36 (d, J = 4.2 Hz, 1H). 13C{H} NMR (100 MHz, CDCl
) δ 150.3, 147.7, 147.3,
3
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137.3, 132.9, 131.6, 129.4, 128.8, 128.7, 128.0

2, 122.1, 120.9. HRMS (ESI, m/z):
10BrN: [M+H] = 284.0069; found: 284.0065.
-methyl-4-phenylquinoline(2p).10a White solid (46.5 mg, yield 53%; eluent:
petroleum ether /EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
) δ 8.85 (s, 1H),
8.11 (d, J = 8.4 Hz, 1H), 7.66-7.60 (m, 1H), 7.55-7.42 (m, 4H), 7.42-7.35 (m, 1H),
+
Calcd. for C15
H
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
7
1
.25-7.27 (m, 2H), 2.27 (s, 3H). 13C{H} NMR (100 MHz, CDCl
) δ 152.6, 146.8,
3
46.2, 136.8, 129.3, 129.2, 128.6, 128.2, 128.0, 127.9, 127.5, 126.4, 125.8, 17.57.
+
HRMS (ESI, m/z): Calcd. for C16
H
3
N: [M+H] = 220.1126; found: 220.1129.
4-(4-fluorophenyl)quinoline(2q).39 White solid (56.2 mg, yield 63%; eluent:
petroleum ether /EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
) δ 8.82 (d, J =
4.4 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.61 (t, J = 7.6 Hz,
H), 7.42-7.30 (m, 3H), 7.18 (d, J = 4.4 Hz, 1H), 7.10 (t, J = 8.6 Hz, 2H). 13C{H}
NMR (100 MHz, CDCl ) δ 162.9(d, J = 246.7 Hz), 149.8, 148.6, 147.3, 133.9 (d, J
3
1
3
= 3.4 Hz), 131.3 (d, J = 8.0 Hz), 129.9, 129.4, 126.8, 126.7, 125.6, 121.4, 115.6(d,
+
J = 21.5 Hz). HRMS (ESI, m/z): Calcd.. for C15
H
10FN: [M+H] = 224.0875; found:
224.0875.
4
-phenyl-6-(trifluoromethyl)quinoline(2r).38 White solid (18.0 mg, yield 11%;
eluent: petroleum ether /EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
) δ
.06 (d, J = 4.4 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.25 (s, 1H), 7.91 (d, J = 8.8 Hz,
3
9
1H), 7.61-7.27 (m, 6H). 13C{H} NMR (100 MHz, CDCl
) δ 152.0, 149.7, 149.6,
3
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1
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1
1
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
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5
5
5
5
5
5
5
5
6
137.0, 131.2, 129.5, 129.0, 128.9, 128.4(q), 126.0, 125.3, 125.1, 124.0, 122.6,
+
1
2
22.4. HRMS (ESI, m/z): Calcd. for C16
H
10
F
3
N: [M+H] = 274.0838; found:
74.0812.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
benzophenone( 2w′).40 White solid (90.7 mg, yield 83%; eluent: petroleum ether
/EtOAc = 100:1-40:1, v/v); 1H NMR (400 MHz, CDCl
) δ 7.81 (d, J = 7.3 Hz, 2H),
.59 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H). 13C{H} NMR (100 MHz, CDCl
3
7
3
)
δ 196.8, 137.6, 132.4, 130.1, 128.3. HRMS (ESI, m/z): Calcd. for C13H10O:
+
[
M+H] = 183.0804; found: 180.0806.
methyl-4-phenyl-1,2,3,4-tetrahydroquinolin-4-ol(2x′).41 White solid (79.8 mg,
yield 78%; eluent: petroleum ether /EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz,
CDCl
3
) δ 7.40 (d, J = 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.27-7.24 (m, 1H), 7.17
(t, J = 7.4 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 6.58 (t, J =
7
.4 Hz, 1H), 3.46 (td, J = 11.3, 3.1 Hz, 1H), 3.11 (m, 1H), 2.97(s, 3H), 2.31-2.23
) δ 148.0, 146.8,
29.2, 129.1, 127.8, 127.7, 126.7, 126.4, 116.5,111.5, 73.3, 47.6, 39.4, 39.2.
(m, 1H), 2.15-2.09 (m, 1H). 13C{H} NMR (100 MHz, CDCl
3
1
+
HRMS (ESI, m/z):Calcd. for C16H17NO: [M+H] = 240.1383; found: 240.1385.
1
H-indole(4a).7b Yellow oil (24.6 mg, yield 35%; eluent: petroleum ether /EtOAc =
0:1-10:1, v/v); 1H NMR (400 MHz, CDCl
) δ 8.15 (br, 1H), 7.66 (d, J = 7.9 Hz,
H), 7.41 (d, J = 8.1 Hz, 1H), 7.18-7.22 (m, 2H), 7.12 (t, J = 7.4 Hz, 1H), 6.57 (s,
4
3
1
1H). 13C{H} NMR (100 MHz, CDCl
) δ 135. 8, 127.9, 124.1, 122.0, 120.7, 119.8,
3
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+
111.0, 102.7. HRMS (ESI, m/z): Calcd. for C
8
H N: [M+H] =118.0651; found:
7
1
18.0653.
-bromo-1H-indole (4b).42 White solid (65.6 mg, yield 48%; eluent: petroleum ether
) δ 8.18 (s, 1H), 7.34-7.13
(m, 3H), 7.06-7.01 (m, 1H), 6.59 (s, 1H). 13C{H} NMR (100 MHz, CDCl
) δ 135.9,
28.6, 124.7, 122.9, 122.7, 114.7, 110.3, 102.9. HRMS (ESI, m/z): Calcd. for
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
/
EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
3
3
1
+
C
8
H BrN: [M+H] =195.9756; found: 195.9753.
6
4
-methyl-1H-indole (4c).22 Yellow oil (48.0 mg, yield 53%; eluent: petroleum ether
/EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
) δ 8.03 (s, 1H), 7.22-7.16 (m,
H), 7.16-7.07 (m, 2H), 6.92 (d, J = 7.0 Hz, 1H), 6.56 (s, 1H), 2.56 (s, 3H). 13C{H}
3
1
NMR (100 MHz, CDCl
3
) δ 135.4,130.2, 127.7, 123.5, 122.1, 119.9, 108.6, 101.2,
+
18.8. HRMS (ESI, m/z): Calcd. for C
9
H
9
N: [M+H] =132.0808; found: 132.0809.
4
-chloro-1H-indole (4d).43
Y
ellow oil (57.0 mg, yield 63%; eluent: petroleum ether
) δ 8.18 (s, 1H), 7.28-7.15
(m, 2H), 7.14-7.03 (m, 2H), 6.65 (s, 1H). 13C{H} NMR (100 MHz, CDCl
) δ 136.4,
26.7, 126.0, 124.7, 122.6, 119.6, 109.7, 101.3. HRMS (ESI, m/z): Calcd. for
/
EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
3
3
1
+
C
8
H ClN: [M+H] =132.0808; found: 132.0809.
6
5
-fluoro-1H-indole (4e).42 White solid (47.0 mg, yield 58%; eluent: petroleum ether
/EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
) δ 8.13 (s, 1H), 7.32-7.26 (m,
H), 7.26-7.22 (m, 1H), 6.95 (td, J = 9.1, 2.4 Hz, 1H), 6.54-6.48 (m, 1H). 13C{H}
3
2
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8
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NMR (100 MHz, CDCl
3
) δ 159.3, 157.1, 132.2, 128.4, 128.0, 125.8, 111.6, 111.5,
110.6, 110.3, 105.6, 105.3, 102.9, 102.8. HRMS (ESI, m/z): Calcd. for C
8
6
H FN:
+
[
M+H] =136.0557; found: 136.0561.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
-bromo-1H-indole (4f).17 White solid (48.0 mg, yield 41%; eluent: petroleum ether
) δ 8.12 (s, 1H), 7.76 (s, 1H),
.29-7.12 (m, 3H), 6.48 (s, 1H). 13C{H} NMR (100 MHz, CDCl
) δ 134.4, 129.6,
/EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
3
7
1
3
25.4, 124.8, 123.2, 113.0, 112.4, 102.3. HRMS (ESI, m/z): Calcd. for C
8
6
H BrN:
+
[
M+H] =195.9756; found: 195.9751.
2-methyl-1H-indole (4g).17 White solid (11.8 mg, yield 15%; eluent: petroleum ether
EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
) δ 7.74 (s, 1H), 7.51 (d, J =
7.4 Hz, 1H), 7.24 (t, J = 6.9 Hz, 1H), 7.12-7.02 (m, 2H), 6.20 (s, 1H), 2.40 (s, 3H).
/
3
13C{H}
NMR (100 MHz, CDCl
) δ 135.0, 132.6, 129.0, 120.9, 119.62, 110.2,
3
+
1
00.4, 13.7. HRMS (ESI, m/z): Calcd. for C
132.0803.
1H-indole-7-carbonitrile (4h).44 White solid (53.6 mg, yield 58%; eluent: petroleum
ether /EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
) δ 9.12 (s, 1H), 7.88 (d,
J = 7.9 Hz, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.35 (d, J = 2.5 Hz, 1H), 7.17 (t, J = 7.7
Hz, 1H), 6.65 (d, J = 2.1 Hz, 1H). 13C{H} NMR (100 MHz, CDCl
) δ 136.0, 128.8,
26.5, 126.2, 125.9, 119.7, 117.1, 103.7, 94.2. HRMS (ESI, m/z): Calcd. for
9
H
9
N: [M+H] =132.0808; found:
3
3
1
+
C
H
9 6
N
2
: [M+H] =143.0604; found: 143.0602.
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6-nitro-1H-indole (4i).42 Yellow solid (71.0 mg, yield 65%; eluent: petroleum ether
/
EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
3
) δ 8.74 (s, 1H), 8.41 (s, 1H),
8
.04 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 6.68 (s,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1H). 13C{H} NMR (100 MHz, CDCl
) δ 143.4, 134.3, 132.8, 130.0, 120.6, 115.4,
3
+
1
08.0, 103.7. HRMS (ESI, m/z): Calcd. for C
163.0506.
H-pyrrolo[2,3-b]pyridine(4j).45 White solid (50.3 mg, yield 63%; eluent:
petroleum ether /EtOAc = 40:1-10:1, v/v) to afford 4j as a; 1H NMR (400 MHz,
CDCl ) δ 10.61 (s, 1H), 8.33 (d, J = 3.6 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.37 (s,
1H), 7.10 (dd, J = 7.8, 4.7 Hz, 1H), 6.51 (d, J = 3.0 Hz, 1H). 13C{H} NMR (100
8
H
6
N
2
O
2
: [M+H] =163.0502; found:
1
3
MHz, CDCl
3
) δ 148.7, 142.8, 129.0, 125.0, 120.3, 115.9, 100.9. HRMS (ESI, m/z):
+
Calcd. for C
7
H
6
N
2
: [M+H] =119.0604; found: 119.0608.
Isoquinolin(4k).7b Yellow oil (7.8 mg, yield 10%; eluent: petroleum ether /EtOAc =
40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
) δ 9.26 (s, 1H), 8.53 (d, J = 5.8 Hz,
H), 7.96 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.72-7.66 (m, 1H), 7.65 (d,
J = 5.8 Hz, 1H), 7.63-7.57 (m, 1H). 13C{H} NMR (100 MHz, CDCl
) δ 152.4,
42.7, 135.8, 130.5, 128.6, 127.7, 127.3, 126.5, 120.6. HRMS (ESI, m/z): Calcd.
3
1
3
1
+
for C
9
H N: [M+H] = 130.0651; found: 130.0652.
7
1
-phenyl-isoquinoline(4l).46 White solid (78.0 mg, yield 65%; eluent: petroleum
ether /EtOAc = 40:1-10:1, v/v); 1H NMR (400 MHz, CDCl
) δ 8.51 (d, J = 5.6 Hz,
3
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1H), 8.01 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.53-7.62 (m, 4H),
7
.37-7.46 (m, 4H). 13C{H} NMR (100 MHz, CDCl
) δ 160.7, 142.2, 139.5, 136.8,
3
129.9, 129.8, 128.5, 128.3, 127.5, 127.1, 126.9, 126.7, 119.9. HRMS (ESI, m/z):
0
1
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9
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0
+
Calcd. for C15
H
11N: [M+H] = 206.0969; found: 206.0971.
ASSOCIATED CONTENT
Supporting Information
1
13
DMSO-d experiment, EPR experiment, H NMR and C NMR of the products. This
6
material is available free of charge via the internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
*E-mail:
Hu Cai: caihu@ncu.edu.cn;
Yongfa Xie: xieyf@ncu.edu.cn
ORCID ID
Hu Cai: 0000-0003-2372-3319
Yongfa Xie: 0000-0001-5004-5483
ACKNOWLEDGMENTS
Hu Cai, Ruchun Yang, Yongfa Xie received Funding from the National Natural Science
Foundation of China Grants 21571094 and 21861026, 21676131, 21905127, respectively.
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These Grants are gratefully acknowledged. The authors also thank Prof. Jian-Hua Xu
(Nanjing University) for his help in the suggestion of reaction mechanism.
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