TMSBr-promoted cascade cyclization of ortho-propynol phenyl azides for the synthesis of 4-bromo quinolines and its applications

Article abstract of DOI:10.3390/molecules24213999

Difficult-to-access 4-bromo quinolines are constructed directly from easily prepared ortho-propynol phenyl azides using TMSBr as acid-promoter. The cascade transformation performs smoothly to generate desired products in moderate to excellent yields with good functional groups compatibility. Notably, TMSBr not only acted as an acid-promoter to initiate the reaction, and also as a nucleophile. In addition, 4-bromo quinolines as key intermediates could further undergo the coupling reactions or nucleophilic reactions to provide a variety of functionalized compounds with molecular diversity at C4 position of quinolines.

Full text of DOI:10.3390/molecules24213999

molecules
Article
TMSBr-Promoted Cascade Cyclization of
ortho-Propynol Phenyl Azides for the Synthesis of
4-Bromo Quinolines and Its Applications
Fengyan Jin †, Tao Yang †, Xian-Rong Song, Jiang Bai, Ruchun Yang, Haixin Ding and
Qiang Xiao *
Institute of Organic Chemistry, Jiangxi Science & Technology Normal University, Key Laboratory of Organic
Chemistry, Jiangxi Province, Nanchang 330013, China; jinfengyancg@163.com (F.J.);
tao_yang2019@yeah.net (T.Y.); songxr2015@163.com (X.-R.S.); mtbaijiang@yeah.net (J.B.);
ouyangruchun@yeah.net (R.Y.); dinghaixin0204@yeah.net (H.D.)
* Correspondence: xiaoqiang@tsinghua.org.cn; Tel.: + 86-1376-700-6775
† Co-first author.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 30 September 2019; Accepted: 31 October 2019; Published: 5 November 2019
Abstract: Difficult-to-access 4-bromo quinolines are constructed directly from easily prepared
ortho-propynol phenyl azides using TMSBr as acid-promoter. The cascade transformation performs
smoothly to generate desired products in moderate to excellent yields with good functional groups
compatibility. Notably, TMSBr not only acted as an acid-promoter to initiate the reaction, and also
as a nucleophile. In addition, 4-bromo quinolines as key intermediates could further undergo the
coupling reactions or nucleophilic reactions to provide a variety of functionalized compounds with
molecular diversity at C4 position of quinolines.
Keywords: TMSBr; propargylic alcohols; azides; cascade cyclization; 4-bromo quinolines
1. Introduction
Quinolines are distinctive and significant frameworks which are widely existed in numerous
pharmaceuticals, pesticide molecules, bioactive molecules, and natural products [
1–
8]. Moreover,
such compounds using as ligands play crucial role in synthetic and catalysis chemistry [
9
–
13].
Consequently, developing general and flexible approach towards these heterocycles has attracted
much attention among synthetic chemists. Until now, despite significant achievements having been
made in the construction of functionalized quinolines [14
of 4-halo quinolines are still limited [23 26]. 4-halo quinolines have been widely used as key
synthetic intermediates for the construction of various bioactive molecules or drugs [27 29]. Therefore,
–22], methods for the direct synthesis
–
–
the development of an efficient and versatile strategy towards 4-halo quinolines is highly desirable,
especially through a cascade cyclization, because of the merits of efficiency and atomic economy.
Based on its distinctive bifunctional group characteristics, the cascade reaction of propynols
is an important tactic in organic synthesis, which exerts a significant role in the construction of
functionalized carbo- or heterocyclic compounds [30
developed various efficient methods to construct functionalized heterocyclics through the cascade
cyclization of propargylic alcohols in the presence of acid-promoter [35 44]. For example, we recently
–34]. In the past few years, our group had
–
reported an efficient approach for the construction of 4-chrolo quinolines via the cyclization of
ortho-propynol phenyl azides with TMSCl as acid-promoter [45]. Taking into consideration that the
coupling reaction of chloro-substituted compounds is more difficult than bromo- or iodo-substituted
compounds, the further development of universal approach for the construction of 4-bromo quinolines
is still desirable and necessary. Herein, we report a general TMSBr-promoted the cascade cyclization
Molecules 2019, 24, 3999; doi:10.3390/molecules24213999
www.mdpi.com/journal/molecules

Molecules 2019, 24, 3999
2 of 15
of ortho-propynol phenyl azides for constructing 4-bromo quinolines, which can further undergo the
coupling reactions or nucleophilic reactions to provide a variety of functionalized compounds with
molecular diversity at C4 position of quinolines (Scheme 1). Compared to the Shvartsberg’s method [26],
our developed strategy has the merits of good functional groups compatibility, easy preparation of the
starting material, and simple operation.
Scheme 1. Our strategy for the construction of 4-bromo quinolines and its applications.
2. Results and Discussion
Initially, the reaction conditions were optimized for cascade cyclization of ortho-propynol phenyl
azides 1a in the presence of TMSBr. Various solvents, temperatures, and TMSBr loading were
investigated, and all cases were shown in Table 1. To our delight, with 2.5 equiv of TMSBr in different
solvents—such as MeCN, CH3NO2, DCE, 1,4-dioxane, HOAc, and DCM—all reactions proceeded
smoothly and cleanly to produce expected product 4-bromo-2-(4-methoxyphenyl)quinoline 2a (Table 1,
entries 1–5); CH3NO2 as solvent was most suitable for this transformation (73% yield). Encouraged
by this preliminary result, further efforts were then directed toward improving the yield of desired
product 2a while suppressing the classical Meyer–Schuster rearrangement side reaction. Our studies
on the loading of TMSBr with CH3NO2 as solvent showed that 3.5 equiv of TMSBr was the most
efficient for this cascade transformation and could improve the yield of product 2a to 81% (Table 1,
entries 6–8). Subsequently, the examination of the reaction temperature indicated that the choice
of reaction temperature was also an important in this transformation (entries 9, 10). Furthermore,
no better yield was obtained when hydrobromic acid (HBr, 48 wt % in H2O) was used instead of TMSBr
as the acid promoter (entry 11). Therefore, we establish the reaction conditions as optimum: 0.2 mmol
of 2-propynol phenyl azides, 3.5 equiv of TMSBr in CH3NO2 were stirred at 60 ◦C.

Molecules 2019, 24, 3999
3 of 15
Table 1. Optimization of the reaction for the synthesis of 2a a.
Entry
Solvent
TMSBr (x Equiv)
T [◦C]
Yield [%]
1
2
3
4
5
6
7
8
9
DCE
MeCN
2.5
2.5
2.5
2.5
2.5
3.5
3.0
2.0
3.5
3.5
3.5
60
60
40
60
60
60
60
60
80
rt
45
39
15
73
36
81
78
67
82
69
75
CH2Cl2
MeNO2
HOAc
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
10
11 b
60
a Unless otherwise noted, all reactions were performed with 0.2 mmol of 1a in solvent (2.0 mL) for 1.0 h. b hydrobromic
acid instead of TMSBr was used.
Then, we investigated the generality of the reaction with diverse substituted propynols
1
using TMSBr as acid-promoter and nucleophile, and the results are presented in Figure 1. Various
substituents R1 and R2 on the aryl ring were well-tolerated under the optimal conditions, efficiently
generating the corresponding products 4-bromo quinolines in favorable yields (up to 91% yield).
Firstly, we investigated the influence of substituent electronic effects on this reaction, and the results
indicated that substrates containing electron-donor groups (OMe, Me) gave better transformation than
those containing electron-poor groups (F, Cl, Br). This might due to the fact that the reaction involved
the carbocation intermediate (Intermediate B, see Scheme 4); and the electron-rich groups were good
for the stabilization of carbocation intermediate. The corresponding products 4-bromo quinolines give
the better yields compared to the synthesis of 4-chrolo quinolines bearing the electron-withdrawing
groups. Substrates bearing ortho-position substituent provided slightly lower yields (2j–2k), indicating
that the steric effect showed clear influence on this reaction. Importantly, the functionalities of halogen
atoms such as fluorine, chlorine, and bromine were also tolerated for this transformation producing
the target products. Such halogenated products could be converted into a variety of functionalized
quinolines through cross-coupling reactions. Substrates containing two or three substituents attached
to the benzene ring smoothly, and the target compounds were generated in good to excellent yields.
Notably, the substrates with naphthyl or styryl group (1m and 1o) were also compatible to generate
the target products in good yields (2k
another aromatic ring on this transformation. Both electron-rich and electron-poor substituents were
performed smoothly to produce the target compounds in 76–89% yields (2m 2s). It was noteworthy
–
2m). Then we examined the effect of a substituent (R2) on
–
that the strong electron-deficient groups (CN and CF3) in R2 also proceeded well in this reaction
and provided the target products in good yields. Unfortunately, no target product 2t was generated
when alkyl-substituted substrate 1t was performed under the optimal conditions. Having successfully
accomplished the direct formation of 4-bromo-quinolines, this cascade reaction was further extended
to the construction of 4-iodo quinolines by using 2-propynol phenyl azides as starting materials with
TMSI in CH3NO2 at 60 ◦C for 1.0 h under these circumstances. Some selected substrates (1a
, 1b, 1n)
were tolerated smoothly to the corresponding 4-iodo quinolines in moderate yields.

Molecules 2019, 24, 3999
4 of 15
a
a
Figure 1. Transformation of ortho-propynol phenyl azides
otherwise noted, all reactions were performed with
(0.2 mmol) in CH3NO2 (2.0 mL) at 60 ◦C for 1 h.
Isolated yield.
1
to 4-bromo quinolines
2
.
Unless
1
Furthermore, the synthetic utility of this TMSBr-promoted reaction of ortho-propynol azides was
demonstrated by a gram-scale synthesis (Scheme 2-1). The yield of product 2a was not obvious affected
when a gram-scale (5 mmol, 1.40g) experiment of 1a was performed under similar reaction conditions.
Importantly, a bromine atom at the 4-position of obtained product quinolines moiety is useful and
easily substituted by various functional hydrocarbon and heteroatomic groups, which persuades

Molecules 2019, 24, 3999
5 of 15
us to exploit synthetic transformation of 4-bromo quinolones [46
–
48]. As representative examples,
the Suzuki coupling reaction of 2a with arylboronic acids to 4-aryl quinolines 3a–3d in good yield
was achieved (Scheme 2-2) [46]. Notably, the corresponding product 4-vinyl quinoline 3e was also
generated when the reaction of 2a with E-phenylethenylboronic acid. Furthermore, the Sonogashira
coupling of 2a with arylacetylene could smoothly proceed to produce the target products 4a
yields (Scheme 2-3) [47]. More importantly, the classical reduction reaction of 2a to the corresponding
quinoline was also investigated (Scheme 2-4). These results clearly demonstrate the usefulness of our
–4b in good
5
obtained product 4-bromo quinolines as synthetic intermediates.
Scheme 2. Functionality elaboration of 4-bromo-quinolines.
As we all known, 4-aryloxy quinolines are significant structure frameworks which are existed
widely in various bioactive molecules and natural products [49–52]. In this context, the synthesis of

Molecules 2019, 24, 3999
6 of 15
4-aryloxy quinolines from 4-bromo quinolines is attractive because of the clean conversion and the
mild reaction conditions. Therefore, the scope of the reactions was also investigated by varying the
phenols. Some representative substituted 4-aryllkoxy quinolines 6a–6d were generated in acceptable
yields by choosing the appropriate nucleophilic reagents (Scheme 3).
Scheme 3. Transformation of 4-bromo quinoline 2a to 4-aryloxy quinolines 6.
On the basis of the above experimental results and literature reports [45
,53,54], we propose a
plausible reaction mechanism for this reaction (Scheme 4). Firstly, a proargylic carbocation intermediate
A
A
was formed through the TMSBr-promoted the dehydration of propargylic alcohols
could easily undergo tautomerization to generate allenic carbocation intermediate , which could be
. Subsequently, the 6-endo-trig
in the presence of proton forms intermediate . Finally, the target product
was generated through the aromatization of the intermediate with the generation of a nitrogen gas
1. Intermediate
B
attracted by nucleophile halide anion (Br−) to produce intermediate
C
cyclization of intermediate
2
C
D
D
and a proton.
Scheme 4. Proposed reaction mechanism.
3. Materials and Methods
3.1. General Remarks
1H-NMR spectra were recorded on 400 MHz in CDCl3 and 13C-NMR spectra were recorded
on 100 MHz in CDCl3. Chemical shifts (ppm) were recorded with tetramethylsilane (TMS) as the
internal reference standard. Multiplicities are given as: s (singlet), d (doublet), t (triplet), dd (doublet
of doublets), q (quartet), or m (multiplet). High-resolution mass spectrometry (HRMS) was performed
on a TOF/Q–TOF mass spectrometer. Copies of the 1H-NMR and 13C-NMR spectra are provided in

Molecules 2019, 24, 3999
7 of 15
the Supporting Information. Commercially available reagents were used without further purification.
All solvents were dried under standard method.
3.2. General Procedure for the Construction of 4-Bromo Quinolines 2
To a seal tub◦e was added ortho-propynol phenyl azides (
1) (0.2 mmol), TMSBr (0.7 mmol),
in CH3NO2 at 60 C. After 1.0 h, as monitored by TLC, the reaction mixture was concentrated in
vacuum and purified by column chromatography to generate 4-bromo quinolines 2.
4-Bromo-2-(4-Methoxyphenyl)quinoline (2a)
The title compound was prepared according to the 0.5, 130.8, 134.5, 148.7, 156.7, 161.1. general
procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give
1
a product 2a (81%) [45]. H-NMR (400 MHz, CDCl3):
δ 3. 79 (s, 3 H), 6.95 (dd, J = 2.0, 6.8 Hz, 2 H),
7.47–7.51 (m, 1 H), 7.63–7.67 (m, 1 H), 8.01–8.07 (m, 5 H). 13C-NMR (100 MHz, CDCl3):
126.3, 126.5, 127.0, 128.9, 129.8, 13.
δ 55.4, 122.4,
4-Bromo-2-(p-tolyl)quinoline (2b)
The title compound was prepared according to the general procedure and purified by column
1
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2b (91%). H-NMR (400
MHz, CDCl3):
δ
2.34 (s, 3 H), 7.23 (d, J = 8.4 Hz, 2 H), 7.48–7.52 (m, 1 H), 7.64–7.68 (m, 1 H), 7.95 (d,
21.3, 122.7, 126.5, 127.2, 127.4, 129.6,
J = 8.0 Hz, 2 H), 8.04–8.08 (m, 3 H). 13C-NMR (100 MHz, CDCl3):
δ
130.0, 130.4, 134.5, 135.5, 139.9, 148.7, 157.1. HRMS (ESI, m/z): calcd for C16H12BrN: M + H = 298.0226;
found: 298.0229.
4-Bromo-2-(m-tolyl)quinoline (2c)
The title compound was prepared according to the general procedure and purified by column
1
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2c (81%). H-NMR (400
MHz, CDCl3):
7.68 (t, J = 7.6 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.89 (s, 1 H), 8.07–8.10 (m, 3 H). 13C-NMR (100 MHz,
CDCl3): 21.5, 123.0, 124.6, 126.5, 126.6, 127.4, 128.2, 128.8, 130.0, 130.5, 130.6, 134.5, 138.3, 138.6, 148.7,
δ 2.39 (s, 3 H), 7.21 (d, J = 7.2 Hz, 1 H), 7.33 (t, J = 7.6 Hz, 1 H), 7.52 (t, J = 7.2 Hz, 1 H),
δ
157.4. HRMS (ESI, m/z): calcd for C16H12BrN: M + H = 298.0226; found: 298.0229.
4-Bromo-2-(o-tolyl)quinoline (2d)
The title compound was prepared according to the general procedure and purified by column
1
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2d (52%). H-NMR (400
MHz, CDCl3):
δ
2.35 (s, 3 H), 7.20–7.29 (m, 3 H), 7.41 (d, J = 6.8 Hz, 1 H), 7.58 (t, J = 7.6 Hz, 1 H), 7.70 (t,
20.3, 126.1, 126.1, 126.3,
J = 7.6 Hz, 1 H), 7.78 (s, 1 H), 8.06–8.16 (m, 2 H). 13C-NMR (100 MHz, CDCl3):
δ
126.6, 127.6, 128.9, 129.6, 130.0, 130.5, 131.1, 133.9, 136.1, 139.4, 148.4, 160.0. HRMS (ESI, m/z): calcd for
C16H12BrN: M + H = 298.0226; found: 298.0227.
4-Bromo-2-phenylquinoline (2e)
The title compound was prepared according to the general procedure and purified by column
1
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2e (46%). H-NMR (400
MHz, CDCl3):
(100 MHz, CDCl3):
δ
7.40–7.48 (m, 3 H), 7.54–7.56 (m, 1 H), 7.67–7.71 (m, 1 H), 8.05–8.11 (m, 5 H). 13C-NMR
δ
122.9, 126.5, 126.7, 127.5, 127.5, 128.9, 129.8, 130.1, 130.5, 134.6, 138.4, 148.8, 157.2.
HRMS (ESI, m/z): calcd for C15H10BrN: M + H = 284.0069; found: 284.0071.
4-Bromo-2-(4-fluorophenyl)quinoline (2f)
The title compound was prepared according to the general procedure and purified by column
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2f (75%). 1H-NMR
(400 MHz, CDCl3):
δ 7.11–7.18 (m, 2 H), 7.52–7.56 (m, 1 H), 7.67–7.71 (m, 1 H), 8.05–8.11 (m, 5 H).

Molecules 2019, 24, 3999
8 of 15
13C-NMR (100 MHz, CDCl3):
δ
115.8, 116.0, 122.5, 126.6, 127.5, 129.4, 129.5, 130.0, 130.7, 134.5, 134.8,
148.7, 156.0, 162.8, 165.3. HRMS (ESI, m/z): calcd for C15H9BrFN: M + H = 301.9975; found: 301.9973.
4-Bromo-2-(4-chlorophenyl)quinoline (2g)
The title compound was prepared according to the general procedure and purified by column
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2g (86%). 1H-NMR
(400 MHz, CDCl3):
δ
7.41 (d, J = 8.4 Hz, 2 H), 7.52–7.56 (m, 1 H), 7.67–7.71 (m, 1 H), 7.99–8.10 (m, 5 H).
122.5, 126.6, 126.7, 127.7, 128.7, 129.1, 130.0, 130.7, 134.8, 136.0, 136.7,
13C-NMR (100 MHz, CDCl3):
δ
148.7, 155.8. HRMS (ESI, m/z): calcd for C15H9BrClN: M + H = 317.9680; found: 317.9682.
4-Bromo-2-(4-bromophenyl)quinoline (2h)
The title compound was prepared according to the general procedure and purified by column
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2h (72%). 1H-NMR
(400 MHz, CDCl3):
δ
7.54–7.57 (m, 3 H), 7.68 (t, J = 8.4 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 2 H), 8.04–8.10 (m,
122.4, 124.5, 126.6, 126.7, 127.7, 129.0, 130.1, 130.7, 132.0, 134.8,
3 H). 13C-NMR (100 MHz, CDCl3):
δ
137.2, 148.7, 155.9. HRMS (ESI, m/z): calcd for C15H9Br2N: M + H = 361.9175; found: 361.9179.
4-Bromo-2-(3,4-dichlorophenyl)quinoline (2i)
The title compound was prepared according to the general procedure and purified by column
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2i (61%). 1H-NMR
(400 MHz, CDCl3):
δ
7.50 (d, J = 8.4 Hz, 1 H), 7.54–7.58 (m, 1 H), 7.69–7.73 (m, 1 H), 7.87–7.90 (m,
122.2, 126.4, 126.6,
1 H), 8.02–8.11 (m, 3 H), 8.21 (d, J = 2.0 Hz, 1 H). 13C-NMR (100 MHz, CDCl3):
δ
126.8, 128.0, 129.3, 130.1, 130.8, 130.9, 133.3, 134.1, 135.0, 138.1, 148.6, 154.4. HRMS (ESI, m/z): calcd for
C15H8BrCl2N: M + H = 351.9290; found: 351.9291.
4-Bromo-2-(4-bromo-2-fluorophenyl)quinoline (2j)
The title compound was prepared according to the general procedure and purified by column
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2j (63%). 1H-NMR
(400 MHz, CDCl3):
δ 7.34 (dd, J = 1.6, 6.8 Hz, 1 H), 7.40 (dd, J = 1.6, 8.4 Hz, 1 H) 7.59 (t, J = 7.2 Hz, 1 H),
7.72 (t, J = 7.2 Hz, 1 H), 7.97 (t, J = 7.6 Hz, 1 H), 8.07–8.14 (m, 3 H). 13C-NMR (100 MHz, CDCl3):
δ
119.8, 120.0, 124.1, 124.2, 125.8, 125.9, 126.7, 126.9, 128.1, 128.2, 128.2, 130.0, 130.7, 132.5, 132.6, 134.4,
148.6, 152.6, 159.1, 161.8. HRMS (ESI, m/z): calcd for C15H8Br2FN: M + H = 379.9080; found: 379.9084.
4-Bromo-2-(3,4-dimethoxyphenyl)quinoline (2k)
The title compound was prepared according to the general procedure and purified by column
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2k (88%). 1H-NMR
(400 MHz, CDCl3):
δ
3.87 (s, 3 H), 3.97 (s, 3 H), 6.89 (d, J = 8.4 Hz, 1 H), 7.48–7.56 (m, 2 H), 7.64–7.68 (m,
55.9, 56.0, 110.2, 111.0,
1 H), 7.75 (d, J = 2.0 Hz, 1 H), 8.05–8.08 (m, 3 H). 13C-NMR (100 MHz, CDCl3):
δ
120.3, 122.5, 126.4, 126.5, 127.1, 129.8, 130.5, 131.0, 134.5, 148.6, 149.4, 150.7, 156.6. HRMS (ESI, m/z):
calcd for C17H14BrNO2: M + H = 344.0281; found: 344.0283.
4-Bromo-2-(3,4,5-trimethoxyphenyl)quinoline (2l)
The title compound was prepared according to the general procedure and purified by column
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2l (86%). 1H-NMR
(400 MHz, CDCl3):
δ
3.85 (s, 3 H), 3.93 (s, 6 H), 7.29 (s, 2 H), 7.53 (t, J = 7.2 Hz, 1 H), 7.69 (t, J = 7.6 Hz
,
1 H), 8.04 (s, 1 H), 8.07–8.10 (m, 2 H). 13C-NMR (100 MHz, CDCl3):
δ
56.3, 60.9, 104.8, 122.7, 126.5, 127.5,
129.9, 130.6, 133.8, 134.6, 139.8, 148.5, 153.6, 156.7. HRMS (ESI, m/z): calcd for C18H16BrNO3: M + H =
374.0386; found: 374.0382.
4-Bromo-2-(naphthalen-1-yl)quinoline (2m)

Molecules 2019, 24, 3999
9 of 15
The title compound was prepared according to the general procedure and purified by column
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2m (81%). 1H-NMR
(400 MHz, CDCl3):
7.86–7.91 (m, 2 H), 7.96 (s, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 8.19 (dd, J = 8.8 Hz, 2 H). 13C-NMR (100 MHz,
CDCl3): 125.3, 126.1, 126.6, 126.7, 126.9, 127.0, 127.9, 128.0, 128.5, 129.6, 129.9, 130.8, 131.0, 133.9, 134.4,
δ 7.41–7.48 (m, 2 H), 7.51–7.55 (m, 1 H), 7.61–7.66 (m, 2 H), 7.56 (t, J = 7.2 Hz, 1 H),
δ
137.1, 148.4, 159.1. HRMS (ESI, m/z): calcd for C19H12BrN: M + H = 334.0226; found: 334.0227.
4-Bromo-2-(naphthalen-2-yl)quinoline (2n)
The title compound was prepared according to the general procedure and purified by column
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2n (84%). 1H-NMR
(400 MHz, CDCl3):
(dd, J = 2.8, 5.6 Hz, 2 H), 8.08–8.11 (m, 2 H), 8.22–8.24 (m, 2 H), 8.47 (d, J = 0.8 Hz, 1 H). 13C-NMR
(100 MHz, CDCl3): 123.0, 124.7, 126.4, 126.6, 126.7, 126.9, 127.3, 127.5, 127.7, 128.7, 128.8, 130.1, 130.6,
δ 7.42–7.46 (m, 2 H), 7.50–7.54 (m, 1 H), 7.66–7.70 (m, 1 H), 7.78–7.81 (m, 1 H), 7.88
δ
133.3, 134.0, 134.6, 135.6, 148.8, 156.9. HRMS (ESI, m/z): calcd for C19H12BrN: M + H = 334.0226;
found: 334.0227.
4-Bromo-2-(4-methoxyphenyl)-6-methylquinoline (2o)
The title compound was prepared according to the general procedure and purified by column
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2o (89%). 1H-NMR
(400 MHz, CDCl3):
δ
2.48 (s, 3 H), 3.79 (s, 3 H), 6.94 (d, J = 8.8 Hz, 2 H), 7.47 (dd, J = 1.6, 8.4 Hz, 1 H),
21.7, 55.3,
7.80 (s, 1 H), 7.91 (d, J = 8.8 Hz, 1 H), 7.98–8.00 (m, 3 H). 13C-NMR (100 MHz, CDCl3):
δ
114.2, 122.4, 125.3, 126.2, 128.7, 129.6, 131.1, 132.6, 133.7, 137.2, 147.3, 155.8, 160.9. HRMS (ESI, m/z):
calcd for C17H14BrNO: M + H = 328.0332; found: 328.0331.
4-Bromo-6-fluoro-2-(4-methoxyphenyl)quinoline (2p)
The title compound was prepared according to the general procedure and purified by column
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2p (83%). 1H-NMR
(400 MHz, CDCl3):
δ
3.81 (s, 3 H), 6.95 (d, J = 8.4 Hz, 2 H), 7.39–7.44 (m, 1 H), 7.70 (dd, J = 2.8, 9.6 Hz,
55.4, 110.2, 110.4, 114.3, 120.5, 120.7, 123.0,
1 H), 7.99–8.05 (m, 4 H). 13C-NMR (100 MHz, CDCl3):
δ
127.2, 127.3, 128.8, 130.6, 132.4, 132.5, 133.3, 133.4, 145.8, 156.1, 156.2, 159.7, 161.2, 162.2. HRMS (ESI,
m/z): calcd for C16H11BrFNO: M + H = 332.0081; found: 332.0081.
4-Bromo-6-chloro-2-(4-methoxyphenyl)quinoline (2q)
The title compound was prepared according to the general procedure and purified by column
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2q (76%). 1H-NMR
(400 MHz, CDCl3):
δ
3.80 (s, 3 H), 6.95 (d, J = 8.8 Hz, 2 H), 7.57 (dd, J = 2.4, 8.8 Hz, 1 H), 7.94–8.05 (m,
55.4, 114.3, 123.1, 125.5, 127.0, 128.8, 130.4, 131.4, 131.5, 133.0, 133.1,
5 H). 13C-NMR (100 MHz, CDCl3):
δ
147.1, 156.9, 161.3. HRMS (ESI, m/z): calcd for C16H11BrClNO: M + H = 347.9785; found: 347.9787.
4-Bromo-2-(4-methoxyphenyl)-6-(trifluoromethyl)quinoline (2r)
The title compound was prepared according to the general procedure and purified by column
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2r (87%). 1H-NMR
(400 MHz, CDCl3):
δ
3.80 (s, 3 H), 6.94 (d, J = 8.8 Hz, 2 H), 7.79 (d, J = 8.8 Hz, 1 H), 8.03 (d, J = 8.4 Hz
,
2 H), 8.10 (d, J = 8.4 Hz, 2 H), 8.34 (s, 1 H). 13C-NMR (100 MHz, CDCl3):
δ
55.4, 114.4, 123.4, 124.6,
124.7, 125.5, 126.1, 126.1, 129.1, 130.0, 131.0, 135.0, 149.7, 158.6, 161.7. HRMS (ESI, m/z): calcd for
C17H11BrF3NO: M + H = 382.0049; found: 382.0045.
4-Bromo-2-(4-methoxyphenyl)quinoline-6-carbonitrile (2s)
The title compound was prepared according to the general procedure and purified by column
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2s (79%). 1H-NMR
(400 MHz, CDCl3):
δ 3.83 (s, 3 H), 6.98 (d, J = 8.8 Hz, 2 H), 7.79 (dd, J = 1.6, 8.4 Hz, 1 H), 8.08 (dd,

Molecules 2019, 24, 3999
10 of 15
J = 5.6, 8.8 Hz, 3 H), 8.16 (s, 1 H), 8.47 (d, J = 1.2 Hz, 1 H). 13C-NMR (100 MHz, CDCl3):
δ
55.5, 110.4,
114.5, 118.5, 123.8, 126.0, 129.3, 129.7, 131.2, 131.3, 132.9, 134.5, 149.9, 159.4, 162.0. HRMS (ESI, m/z):
calcd for C17H11BrN2O: M + H = 339.0128; found: 339.0128.
4-Iodo-2-(4-methoxyphenyl)quinoline (2u)
The title compound was prepared according to the general procedure and purified by column
1
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2u (62%) [45]. H-NMR
(400 MHz, CDCl3):
δ 3.89 (s, 3 H), 7.03–7.05 (m, 2 H), 7.54–7.58 (m, 1 H), 7.70–7.74 (m, 1 H), 7.98 (d,
J = 8.4 Hz, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 8.09–8.12 (m, 2 H), 8.42 (s, 1 H). 13C-NMR (100 MHz, CDCl3):
δ 66.4, 112.5, 114.3, 127.4, 128.9, 128.9, 130.1, 130.1, 130.5, 130.6, 131.4, 147.8, 156.7, 161.1.
4-Iodo-2-(p-tolyl)quinoline (2v)
The title compound was prepared according to the general procedure and purified by column
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2v (56%). 1H-NMR
(400 MHz, CDCl3): 2.44 (s, 3 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.60 (t, J = 7.2 Hz, 1 H), 7.72–7.76 (m, 1 H),
7.99–8.08 (m, 4 H), 8.45 (s, 1 H). 13C-NMR (100 MHz, CDCl3):
δ 21.3, 112.5, 127.4, 127.6, 129.0, 129.7,
130.2, 130.4, 130.5, 131.4, 135.2, 139.9, 147.8, 157.0. HRMS (ESI, m/z): calcd for C16H12IN: M + H =
346.0087; found: 346.0092.
4-Iodo-2-(naphthalen-2-yl)quinoline (2w)
The title compound was prepared according to the general procedure and purified by column
chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2w (67%). 1H-NMR
(400 MHz, CDCl3):
7.99–8.05 (m, 3 H), 8.14 (d, J = 8.4 Hz, 1 H), 8.32–8.35 (m, 1 H), 8.59 (s, 1 H), 8.63 (s, 1 H). 13C-NMR
(100 MHz, CDCl3): 112.6, 124.8, 126.5, 126.9, 127.3, 127.7, 127.9, 128.7, 128.8, 129.2, 130.3, 130.6,
δ 7.54–7.57 (m, 2 H), 7.60–7.64 (m, 1 H), 7.75–7.80 (m, 1 H), 7.90–7.92 (m, 1 H),
δ
130.7, 131.5, 133.4, 134.0, 135.3, 147.9, 156.9. HRMS (ESI, m/z): calcd for C19H12IN: M + H = 382.0087;
found: 382.0089.
2-(4-Methoxyphenyl)-4-(p-tolyl)quinoline (3a)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl
1
acetate) to give a product 3a (58%) [55]. H-NMR (400 MHz, CDCl3):
δ 2.38 (s, 3 H), 3.78 (s, 3 H), 6.95
(d, J = 8.4 Hz, 2 H), 7.26 (d, J = 8.0 Hz, 2 H), 7.32–7.37 (m, 3 H), 7.59–7.63 (m, 1 H), 7.66 (s, 1 H), 7.81 (d,
J = 8.4 Hz, 1 H), 8.05–8.12 (m, 3 H). 13C-NMR (100 MHz, CDCl3):
δ
21.3, 55.3, 114.2, 118.8, 125.6, 125.7,
125.8, 128.9, 129.2, 129.3, 129.4, 129.8, 132.3, 135.6, 138.2, 148.8, 149.0, 156.4, 160.8.
2,4-bis(4-Methoxyphenyl)quinoline (3b)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl
1
acetate) to give a product 3b (71%) [55]. H-NMR (400 MHz, CDCl3):
δ 3.79 (s, 3 H), 3.81 (s, 3 H), 6.97
(dd, J = 8.8, 13.2 Hz, 4 H), 7.33–7.37 (m, 1 H), 7.41 (d, J = 8.8 Hz, 2 H), 7.59–7.63 (m, 1 H), 7.66 (s, 1 H),
7.82 (d, J = 8.4 Hz, 1 H), 8.06–8.12 (m, 3 H). 13C-NMR (100 MHz, CDCl3):
δ
55.3, 55.4, 114.0, 114.2, 118.8,
125.6, 125.7, 125.8, 128.9, 129.3, 129.8, 130.7, 132.3, 148.6, 148.9, 156.4, 159.8, 160.8.
4-(4-Fluorophenyl)-2-(4-methoxyphenyl)quinoline (3c)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl
1
acetate) to give a product 3c (66%) [55]. H-NMR (400 MHz, CDCl3):
δ 3.80 (s, 3 H), 6.96 (d, J = 8.8 Hz,
2 H), 7.13–7.18 (m, 2 H), 7.35–7.39 (m, 1 H), 7.43–7.46 (m, 2 H), 7.61–7.65 (m, 2 H), 7.73 (d, J = 8.4 Hz
,
1 H), 8.06–8.13 (m, 3 H). 13C-NMR (100 MHz, CDCl3):
δ
55.4, 114.2, 115.5, 115.7, 118.9, 125.3, 125.5,
126.0, 128.9, 128.5, 130.0, 131.2, 131.3, 132.0, 134.4, 134.5, 147.9, 148.8, 156.4, 160.9, 161.6, 164.1.
4-(3,5-Dimethylphenyl)-2-(4-methoxyphenyl)quinoline (3d)

Molecules 2019, 24, 3999
11 of 15
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl
1
acetate) to give a product 3d (62%). H-NMR (400 MHz, CDCl3):
δ 2.34 (s, 6 H), 3.79 (s, 3 H), 6.95 (d,
J = 8.8 Hz, 2 H), 7.05–7.08 (m, 3 H), 7.33–7.37 (m, 1 H), 7.59–7.63 (m, 1 H), 7.67 (s, 1 H), 7.81 (d, J = 8.4
Hz, 1 H), 8.06–8.12 (m, 3 H). 13C-NMR (100 MHz, CDCl3):
δ
21.3, 55.3, 114.2, 118.7, 125.6, 125.7, 125.8,
127.3, 128.9, 129.3, 129.8, 129.9, 132.2, 138.1, 138.4, 148.7, 149.3, 156.4, 160.8. HRMS (ESI, m/z): calcd for:
C24H21NO: M + H = 340.1696; found: M + H = 340.1692.
(E)-2-(4-Methoxyphenyl)-4-styrylquinoline (3e)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl
1
acetate) to give a product 3e (72%) [56]. H-NMR (400 MHz, CDCl3):
δ 3.83 (s, 3 H), 6.99 (d, J = 8.4 Hz,
2 H), 7.27–7.39 (m, 4 H), 7.44–7.49 (m, 1 H), 7.58 (d, J = 7.2 Hz, 2 H), 7.63–7.67 (m, 1 H), 7.77 (d, J = 16.0
Hz, 1 H), 7.95 (s, 1 H), 8.08–8.12 (m, 4 H). 13C-NMR (100 MHz, CDCl3):
δ
55.4, 114.2, 114.7, 123.3, 123.6,
125.2, 125.9, 127.1, 128.7, 128.8, 128.9, 129.4, 130.2, 132.4, 134.9, 136.7, 143.5, 148.8, 156.8, 160.8.
2-(4-Methoxyphenyl)-4-((4-methoxyphenyl)ethynyl)quinoline (4a)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl
1
acetate) to give a product 4a (67%) [45]. H-NMR (400 MHz, CDCl3):
δ 3.86 (s, 3 H), 3.89 (s, 3 H), 6.95
(d, J = 8.8 Hz, 2 H), 7.05 (d, J = 8.8 Hz, 2 H), 7.55–7.59 (m, 1 H), 7.63 (d, J = 8.8 Hz, 2 H), 7.71–7.75 (m,
1 H), 8.00 (s, 1 H), 8.13–8.16 (m, 3 H), 8.33 (d, J = 7.6 Hz, 1 H). 13C-NMR (100 MHz, CDCl3):
δ
55.4, 84.5,
98.2, 114.2, 114.2, 114.4, 120.9, 125.7, 126.3, 126.3, 128.8, 129.8, 129.9, 130.5, 131.8, 133.5, 148.2, 156.4,
160.4, 160.9.
4-((3,5-Dimethoxyphenyl)ethynyl)-2-(4-methoxyphenyl)quinoline (4b)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl
1
acetate) to give a product 4b (76%). H-NMR (400 MHz, CDCl3):
δ 3.78 (s, 6 H), 3.82 (s, 3 H), 6.48
(t, J = 2.0 Hz, 1 H), 6.76 (d, J = 2.4 Hz, 2 H), 6.98 (d, J = 8.8 Hz, 2 H), 7.51 (t, J = 7.6 Hz, 1 H), 7.67 (t,
J = 8.0 Hz, 1 H), 7.96 (s, 1 H), 8.07–8.10 (m, 3 H), 8.25 (d, J = 8.0 Hz, 1 H). 13C-NMR (100 MHz, CDCl3):
δ
55.5, 85.0, 97.8, 102.6, 109.7, 114.3, 121.3, 123.6, 125.6, 126.3, 126.5, 128.8, 129.9, 130.0, 130.0, 131.7,
148.2, 156.4, 160.7, 161.0. HRMS (ESI, m/z): calcd for: C26H21NO3: M + H = 396.1594; found: 396.1596.
2-(4-Methoxyphenyl)quinoline (5)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl
1
acetate) to give a product
5
(75%) [57]. H-NMR (400 MHz, CDCl3):
δ
3.79 (s, 3 H), 6.96 (d, J = 8.8 Hz,
2 H), 7.38–7.42 (m, 1 H), 7.59–7.64 (m, 1 H), 7.70–7.75 (m, 2 H), 8.04–8.09 (m, 4 H). 13C-NMR (100 MHz,
CDCl3): δ 55.4, 114.2, 118.5, 125.8, 126.9, 127.4, 128.9, 129.5, 129.5, 132.2, 136.6, 148.3, 156.9, 160.8.
2-(4-Methoxyphenyl)-4-(p-tolyloxy)quinoline (6a)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl
1
acetate) to give a product 6a (32%). H-NMR (400 MHz, CDCl3):
δ 2.35 (s, 3 H), 3.77 (s, 3 H), 6.88–6.90
(m, 3 H), 7.04 (d, J = 8.4 Hz, 2 H), 7.18–7.21 (m, 2 H), 7.44 (t, J = 7.6 Hz, 1 H), 7.66 (t, J = 7.6 Hz, 1 H),
7.84 (d, J = 8.8 Hz, 2 H), 8.04 (d, J = 8.8 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H). 13C-NMR (100 MHz, CDCl3):
δ
20.9, 55.4, 101.7, 114.0, 120.4, 120.7, 121.7, 125.4, 128.8, 129.1, 130.2, 130.7, 132.5, 135.1, 149.8, 152.3,
158.1, 160.7, 162.5. HRMS (ESI, m/z): calcd for: C23H19NO2: M + H = 342.1489; found: 342.1495.
4-(4-Chlorophenoxy)-2-(4-methoxyphenyl)quinoline (6b)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl
1
acetate) to give a product 6b (48%). H-NMR (400 MHz, CDCl3):
δ 3.77 (s, 3 H), 6.89–6.92 (m, 3 H),
7.09 (d, J = 8.8 Hz, 2 H), 7.36 (d, J = 9.2 Hz, 2 H), 7.45 (t, J = 7.2 Hz, 1 H), 7.65–7.70 (m, 1 H), 7.86 (d,
J = 8.8 Hz, 2 H), 8.05 (d, J = 8.4 Hz, 1 H), 8.19 (d, J = 7.6 Hz, 1 H). 13C-NMR (100 MHz, CDCl3):
δ
55.5,
110.4, 114.5, 118.5, 123.8, 126.0, 129.3, 129.7, 131.2, 131.3, 132.9, 134.5, 149.9, 159.4, 162.0. HRMS (ESI,
m/z): calcd for: C22H16ClNO2: M + H = 362.0942; found: 362.0948.

Molecules 2019, 24, 3999
12 of 15
4-(4-Bromophenoxy)-2-(4-methoxyphenyl)quinoline (6c)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl
1
acetate) to give a product 6c (45%). H-NMR (400 MHz, CDCl3):
δ 3.77 (s, 3 H), 6.89–6.93 (m, 3 H), 7.04
(d, J = 8.8 Hz, 2 H), 7.45 (t, J = 7.2 Hz, 1 H), 7.51 (d, J = 8.8 Hz, 2 H), 7.67 (t, J = 8.4 Hz, 1 H), 7.86 (d,
J = 8.4 Hz, 2 H), 8.06 (d, J = 8.4 Hz, 1 H), 8.18 (d, J = 8.0Hz, 1 H). 13C-NMR (100 MHz, CDCl3):
δ
55.4,
102.3, 114.1, 118.2, 120.2, 121.5, 122.5, 125.7, 128.8, 129.2, 130.4, 132.1, 133.3, 149.8, 153.9, 158.1, 160.9,
161.7. HRMS (ESI, m/z): calcd for: C22H16BrNO2: M + H = 406.0437; found: 406.0431.
4-(4-Fluorophenoxy)-2-(4-methoxyphenyl)quinoline (6d)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl
1
acetate) to give a product 6d (53%). H-NMR (400 MHz, CDCl3):
δ 3.77 (s, 3 H), 6.89–6.93 (m, 3 H), 7.04
(d, J = 8.8 Hz, 2 H), 7.45 (t, J = 7.2 Hz, 1 H), 7.51 (d, J = 8.8 Hz, 2 H), 7.67 (t, J = 8.4 Hz, 1 H), 7.86 (d,
J = 8.4 Hz, 2 H), 8.06 (d, J = 8.4 Hz, 1 H), 8.18 (d, J = 8.0Hz, 1 H). 13C-NMR (100 MHz, CDCl3):
δ
55.4,
102.3, 114.1, 118.2, 120.2, 121.5, 122.5, 125.7, 128.8, 129.2, 130.4, 132.1, 133.3, 149.8, 153.9, 158.1, 160.9,
161.7. HRMS (ESI, m/z): calcd for: C22H16FNO2: M + H = 346.1238; found: 346.1234.
4. Conclusions
In summary, we have developed an efficient and general approach for the synthesis of 4-bromo
or 4-iodo quinolines through the TMSBr promoted the cascade cyclization of ortho-propynol phenyl
azides. It is noteworthy that the obtained products 4-halo quinolines could be used as key intermediate
for the construction of various bioactive molecules, natural products, and drugs. A variety of 4-halo
quinolines were obtained in moderate to excellent yields under mild conditions. This process does not
require the use of metal catalysts, additional oxidants; water and nitrogen gas are generated as the
only side products.
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/24/21/3999/s1.
Author Contributions: Conceptualization, Q.X.; Data curation, J.B.; Formal analysis, F.J., T.Y., and X.-R.S.;
Writing—original draft preparation, F.J.; Writing—review and editing, X.-R.S., R.Y., and H.D.
Funding: This work was funded by the National Science Foundation of China (21676131 and 21462019), the Science
Foundation of Jiangxi Province (20181BAB203005 and 20143ACB20012), the Education Department of Jiangxi
Province (GJJ180616), Jiangxi Science & Technology Normal University (2017QNBJRC004).
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
Joule, J.A.; Mills, K. Heterocylic Chemistry, 4th ed.; Blackwell Science, Ltd.: Oxford, UK, 2000; p. 121.
Balasubraimanan, M.; Keay, J.G. Comprehensive Heterocyclic Chemistry II; Katritzky, A.R., Rees, C.W.,
Scriven, E.F.V., Eds.; Pergamon Press: Oxford, UK, 1996; Volume 5, p. 245.
3.
4.
Michael, J.P. Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep. 2008, 25, 166–187. [CrossRef]
Boa, A.N.; Canavan, S.P.; Hirst, P.R.; Ramsey, C.; Stead, A.M.W.; McConkey, G.A. Synthesis of brequinar
analogue inhibitors of malaria parasite dihydroorotate dehydrogenase. Bioorg. Med. Chem. 2005, 13,
1945–1967. [CrossRef]
5.
6.
7.
Diao, Y.; Lu, W.; Jin, H.; Zhu, J.; Han, L.; Xu, M.; Gao, R.; Shen, X.; Zhao, Z.; Liu, X.; et al. Discovery of Diverse
Human Dihydroorotate Dehydrogenase Inhibitors as Immunosuppressive Agents by Structure-Based Virtual
Screening. J. Med. Chem. 2012, 55, 8341–8349. [CrossRef]
Munier-Lehmann, H.; Lucas-Hourani, M.; Guillou, S.; Helynck, O.; Zanghi, G.; Noel, A.; Tangy, F.;
Vidalain, P.; Janin, Y.L. Original 2-(3-Alkoxy-1H-pyrazol-1-yl)pyrimidine Derivatives as Inhibitors of Human
Dihydroorotate Dehydrogenase (DHODH). J. Med. Chem. 2015, 58, 860–877. [CrossRef]
Das, P.; Deng, X.; Zhang, L.; Roth, M.G.; Fontoura, B.M.A.; Phillips, M.A.; De Brabander, J.K. SAR-Based
Optimization of a 4-Quinoline Carboxylic Acid Analogue with Potent Antiviral Activity. ACS Med. Chem.
Lett. 2013, 4, 517–521. [CrossRef]

Molecules 2019, 24, 3999
13 of 15
8.
9.
Strekowski, L.; Say, M.; Zegrocka, O.; Tanious, F.A.; Wilson, W.D.; Manzel, L.; Macfarlane, D.E.
Bis-4-aminoquinolines: Novel triple-helix DNA intercalators and antagonists of immunostimulatory
CpG-oligodeoxynucleotides. Bioorg. Med. Chem. 2003, 11, 1079–1085. [CrossRef]
Gogoi, S.; Zhao, C.-G. Organocatalyzed enantioselective synthesis of 6-amino-5-cyanodihydropyrano[2,3-
c]pyrazoles. Tetrahedron Lett. 2009, 50, 2252–2255. [CrossRef]
10. Tan, B.; Shi, Z.; Chua, J.P.; Zhong, G. Control of Four Stereocenters in an Organocatalytic Domino Double
Michael Reaction: Efficient Synthesis of Multisubstituted Cyclopentanes. Org. Lett. 2008, 10, 3425–3428.
[CrossRef]
11. Wang, B.; Wu, F.; Wang, Y.; Liu, X.; Deng, L. Control of Diastereoselectivity in Tandem Asymmetric Reactions
Generating Nonadjacent Stereocenters with Bifunctional Catalysis by Cinchona Alkaloids. J. Am. Chem. Soc.
2007, 129, 768–769. [CrossRef]
12. Biddle, M.M.; Lin, M.; Scheidt, K.A. Catalytic Enantioselective Synthesis of Flavanones and Chromanones.
J. Am. Chem. Soc. 2007, 129, 3830–3831. [CrossRef]
13. Enders, D.; Grondal, C.; Hüttl, M.R.M. Asymmetric Organocatalytic Domino Reactions. Angew. Chem.
Int. Ed. 2007, 46, 1570–1581. [CrossRef] [PubMed]
14. Bharate, J.B.; Vishwakarma, R.A.; Bharate, S.B. Metal-free domino one-pot protocols for quinoline synthesis.
RSC Adv. 2015, 5, 42020–42053. [CrossRef]
15. Prajapati, S.M.; Patel, K.D.; Vekariya, R.H.; Panchal, S.N.; Patel, H.D. Recent advances in the synthesis of
quinolines: A review. RSC Adv. 2014, 4, 24463–24476. [CrossRef]
16. Hassanin, H.M.; Ibrahim, M.A.; Gabr, Y.A.; Alnamer, Y.A. Synthesis and Chemical Reactivity of
Pyrano[3,2-c]quinolinones. J. Heterocycl. Chem. 2012, 49, 1269–1289. [CrossRef]
17. Wang, Y.; Peng, C.; Liu, L.; Zhao, J.; Su, L.; Zhu, Q. Sulfuric acid promoted condensation cyclization of
2-(2-(trimethylsilyl) ethynyl)anilines with arylaldehydes in alcoholic solvents: An efficient one-pot synthesis
of 4-alkoxy-2-arylquinolines. Tetrahedron Lett. 2009, 50, 2261–2265. [CrossRef]
18. Sridharan, V.; Avendano, C.; Menendez, J.C. CAN-catalyzed three-component reaction between anilines and
alkyl vinyl ethers: Stereoselective synthesis of 2-methyl-1,2,3,4-tetrahydroquinolines and studies on their
aromatization. Tetrahedron 2007, 63, 673–681. [CrossRef]
19. Gharpure, S.J.; Nanda, S.K.; Adate, P.A.; Shelke, Y.G. Lewis Acid Promoted Oxonium Ion Driven
Carboamination of Alkynes for the Synthesis of 4-Alkoxy Quinolines. J. Org. Chem. 2017, 82, 2067–2080.
[CrossRef]
20. Mao, X.-F.; Zhu, X.-P.; Li, D.-Y.; Liu, P.-N. Cu-Catalyzed Cascade Annulation of Alkynols with
2-Azidobenzaldehydes: Access to 6H-Isochromeno [4,3-c]quinoline. J. Org. Chem. 2017, 82, 7032–7039.
[CrossRef]
21. Liu, Y.; Zhang, X.; Xi, C. MeOTf-induced annulation of arylisocyanates and arylalkynes leading to
4-methoxyl-2,3-diarylquinolines. Tetrahedron Lett. 2018, 59, 2440–2442. [CrossRef]
22. Yang, T.; Ding, H.; Li, R.; Jin, F.; Song, X.-R.; Chen, X.; Bai, J.; Xiao, Q.; Liang, Y.-M. para-TsOH-Promoted
Cascade Reaction of ortho-Propynol Phenyl Azides for the Synthesis of 4-Methoxy Quinolines and Propargyl
Methyl Ethers: Insight on Mechanism of Propargylic Alcohols. Asian J. Org. Chem. 2019, 8, 391–398.
[CrossRef]
23. Abbiati, G.; Arcadi, A.; Marinelli, F.; Rossi, E. Domino [3 + 2] Cycloaddition/Annulation Reactions of
β-(2-Aminophenyl)-α,β-ynones with Nitrile Oxides: Synthesis of Isoxazolo[4,5-c]quinolines. Eur. J.
Org. Chem. 2003, 2003, 1423–1427. [CrossRef]
24. Strekowski, L.; Zegrocka, O.; Windham, C.; Czarny, A. Practical Synthesis of 4-Chloro-2-(2-naphthyl)quinoline,
a Precursor to Triple-Helix DNA Intercalators. Org. Process Res. Dev. 1997, 1, 384–386. [CrossRef]
25. Akila, S.; Selvi, S.; Balasubramanian, K. The Vilsmeier cyclization of 20-azido and 20-aminochalcones—A
mild one pot synthesis of 2-aryl-4-chloroquinoline and its N-formyl-1,2-dihydro derivatives. Tetrahedron
2001, 57, 3465–3469. [CrossRef]
26. Shvartsberg, M.S.; Kolodina, E.A. Synthesis of 4-haloquinolines and their fused polycyclic derivatives.
Mendeleev Commun. 2008, 18, 109–111. [CrossRef]
27. O’Neill, P.M.; Bray, P.G.; Hawley, S.R.; Ward, S.A.; Park, B.K. 4-Aminoquinolines—Past, present, and future;
A chemical perspective. Pharmacol. Ther. 1998, 77, 29–58. [CrossRef]

Molecules 2019, 24, 3999
14 of 15
28. Blauer, G.; Akkawi, M.; Fleischhacker, W.; Hiessboeck, R. Synthesis and optical properties of the chloroquine
enantiomers and their complexes with ferriprotoporphyrin IX in aqueous solution. Chirality 1998, 10, 556–563.
[CrossRef]
29. Egan, T.J.; Hunter, R.; Kaschula, C.H.; Marques, H.M.; Misplon, A.; Walden, J. Structure
Relationships in Aminoquinolines: Effect of Amino and Chloro Groups on Quinoline Hematin Complex
-Hematin Formation, and Antiplasmodial Activity. J. Med. Chem. 2000, 43, 283–291.
−Function
−
Formation, Inhibition of
[CrossRef]
β
30. Muzart, J. Gold-catalysed reactions of alcohols: Isomerisation, inter- and intramolecular reactions leading to
C–C and C–heteroatom bonds. Tetrahedron 2008, 64, 5815–5849. [CrossRef]
31. Kabalka, G.W.; Yao, M.-L. Direct Propargylic Substitution of Hydroxyl Group in Propargylic Alcohols.
Curr. Org. Synth. 2008, 5, 28–32. [CrossRef]
32. Zhang, L.; Fang, G.; Kumar, R.K.; Bi, X. Coinage-Metal-Catalyzed Reactions of Propargylic Alcohols. Synthesis
2015, 47, 2317–2346.
33. Zhu, Y.; Sun, L.; Lu, P.; Wang, Y. Recent Advances on the Lewis Acid-Catalyzed Cascade Rearrangements of
Propargylic Alcohols and Their Derivatives. ACS Catal. 2014, 4, 1911–1925. [CrossRef]
34. Song, X.-R.; Qiu, Y.-F.; Liu, X.-Y.; Liang, Y.-M. Recent advances in the tandem reaction of azides with alkynes
or alkynols. Org. Biomol. Chem. 2016, 14, 11317–11331. [CrossRef] [PubMed]
35. Han, Y.-P.; Li, X.-S.; Zhu, X.-Y.; Li, M.; Zhou, L.; Song, X.-R.; Liang, Y.-M. Lewis Acid Catalyzed
Dehydrogenative Coupling of Tertiary Propargylic Alcohols with Quinoline N-Oxides. J. Org. Chem.
2017, 82, 1697–1704. [CrossRef] [PubMed]
36. Han, Y.-P.; Song, X.-R.; Qiu, Y.-F.; Li, X.-S.; Zhang, H.-R.; Zhu, X.-Y.; Liu, X.-Y.; Liang, Y.-M. Lewis Acid
Catalyzed Cyclization of Propargylic Alcohols with 2-Vinylphenol. Org. Lett. 2016, 18, 3866–3869. [CrossRef]
[PubMed]
37. Han, Y.-P.; Song, X.-R.; Qiu, Y.-F.; Zhang, H.-R.; Li, L.-H.; Jin, D.-P.; Sun, X.-Q.; Liu, X.-Y.; Liang, Y.-M. Lewis
Acid Catalyzed [4 + 3] Cycloaddition of Propargylic Alcohols with Azides. Org. Lett. 2016, 18, 940–943.
[CrossRef]
38. Qiu, Y.-F.; Song, X.-R.; Li, M.; Zhu, X.-Y.; Wang, A.-Q.; Yang, F.; Han, Y.-P.; Zhang, H.-R.; Jin, D.-P.; Li, Y.-X.;
et al. BF3 OEt2-AgSCF3 Mediated Trifluoromethylthiolation/Cascade Cyclization of Propynols: Synthesis
·
of 4-((Trifluoromethyl)thio)-2H-chromene and 4-((Trifluoromethyl)thio)-1,2-dihydroquinoline Derivatives.
Org. Lett. 2016, 18, 1514–1517. [CrossRef]
39. Li, R.; Jin, F.; Song, X.-R.; Yang, T.; Ding, H.; Yang, R.; Xiao, Q.; Liang, Y.-M. Acid-promoted cyclization of
2-propynolphenols leading to 4-tosyloxy-2H-chromenes. Tetrahedron Lett. 2019, 60, 331–334. [CrossRef]
40. Yang, T.; Song, X.-R.; Li, R.; Jin, F.; Zhang, Y.; Bai, J.; Yang, R.; Ding, H.; Xiao, Q. Metal-free and efficient
approach to 4-thiocyanated 2H-chromenes via TFA-mediated cascade cyclization of 2-propynolphenols.
Tetrahedron Lett. 2019, 60, 1248–1253. [CrossRef]
41. Li, R.; Song, X.-R.; Chen, X.; Ding, H.; Xiao, Q.; Liang, Y.-M. Copper-Catalyzed Cascade Cyclization of
2-Propynolphenols: Access to 4-Phosphorylated 2H-Chromenes. Adv. Synth. Catal. 2017, 359, 3962–3967.
[CrossRef]
42. Song, X.-R.; Li, R.; Yang, T.; Chen, X.; Ding, H.; Xiao, Q.; Liang, Y.-M. Novel and Efficient Access to
Flavones under Mild Conditions: Aqueous HI-Mediated Cascade Cyclization/Oxidative Radical Reaction of
2-Propynolphenols. Eur. J. Org. Chem. 2018, 2018, 5548–5552. [CrossRef]
43. Yang, T.; Kou, P.; Jin, F.; Song, X.-R.; Bai, J.; Ding, H.; Xiao, Q.; Liang, Y.-M. TFA-Promoted Sulfonation/Cascade
Cyclization of 2-Propynolphenols with Sodium Sulfinates to 4-Sulfonyl 2H-Chromenes under Metal-free
Conditions. Org. Chem. Front. 2019, 6, 3162–3166. [CrossRef]
44. Song, X.-R.; Li, R.; Ding, H.; Yang, R.; Xiao, Q.; Liang, Y.-M. Highly efficient access to
4-chloro-2H-chromenes and 1,2-dihydroquinolines under mild conditions: TMSCl-mediated cyclization of
2-propynolphenols/anilines. Tetrahedron Lett. 2016, 57, 4519–4524. [CrossRef]
45. Song, X.-R.; Li, R.; Ding, H.; Chen, X.; Yang, T.; Jiang, B.; Xiao, Q.; Liang, Y.-M. An efficient approach to 4-chloro
quinolines via TMSCl-mediated cascade cyclization of ortho-propynol phenyl azides. Org. Chem. Front.
2018, 5, 1537–1541. [CrossRef]
46. Wada, T.; Iwasaki, M.; Kondoh, A.; Yorimitsu, H.; Hideki Yorimitsu Oshima, K. Palladium-Catalyzed
Addition of Silyl-Substituted Chloroalkynes to Terminal Alkynes. Chem. Eur. J. 2010, 16, 10671–10674.
[CrossRef]

Molecules 2019, 24, 3999
15 of 15
47. Gopinath, V.S.; Pinjari, J.; Dere, R.T.; Verma, A.; Vishwakarma, P.; Shivahare, R.; Moger, M.; Goud, P.S.K.;
Ramanathan, V.; Bose, P.; et al. Design, synthesis and biological evaluation of 2-substituted quinolines as
potential antileishmanial agents. Eur. J. Med. Chem. 2013, 69, 52. [CrossRef] [PubMed]
48. Gopinath, V.S.; Rao, M.; Shivahare, R.; Vishwakarma, P.; Ghose, S.; Pradhan, A.; Hindupur, R.; Sarma, K.D.;
Gupta, S.; Puri, S.K.; et al. Design, synthesis, ADME characterization and antileishmanial evaluation of novel
substituted quinoline analogs. Bioorg. Med. Chem. Lett. 2014, 24, 2046–2052. [CrossRef]
49. Michael, J.P. Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep. 2001, 18, 543–559. [CrossRef]
50. Michael, J.P. Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep. 2003, 20, 476–493. [CrossRef]
51. Musiol, R.; Serda, M.; Bielowka, S.H.; Polanski, J. Quinoline-Based Antifungals. Curr. Med. Chem. 2010, 17,
1960–1973. [CrossRef]
52. Solomon, V.R.; Lee, H. Quinoline as a Privileged Scaffold in Cancer Drug Discovery. Curr. Med. Chem. 2011
18, 1488–1508. [CrossRef]
,
53. Zhang, H.; Tanimoto, H.; Morimoto, T.; Nishiyama, Y.; Kakiuchi, K. Regioselective Rapid Synthesis of Fully
Substituted 1,2,3-Triazoles Mediated by Propargyl Cations. Org. Lett. 2013, 15, 5222–5225. [CrossRef]
[PubMed]
54. Zhu, Y.; Yin, G.; Hong, D.; Lu, P.; Wang, Y. Tandem Reaction of Propargylic Alcohol, Sulfonamide, and
N-Iodosuccinimide: Synthesis of N-(2-Iodoinden-1-yl)arenesulfonamide. Org. Lett. 2011, 13, 1024–1027.
[CrossRef] [PubMed]
55. Adeloye, A.O.; Mphahlele, M.J. 2,4-Diarylquinolines: Synthesis, absorption and emission properties.
J. Chem. Res. 2011, 35, 254–259. [CrossRef]
56. Abbitati, G.; Arcadi, A.; Marinelli, F.; Rossi, E.; Verdecchia, M. Rh-Catalyzed Sequential Hydroarylation/
Hydrovinylation–Heterocyclization of b-(2-Aminophenyl)-a,b-ynones with Organoboron Derivatives: A New
Approach to Functionalized Quinolines. Synlett 2006, 19, 3218–3224.
57. Azizi, K.; Akrami, S.; Madsen, R. Manganese(III) Porphyrin-Catalyzed Dehydrogenation of Alcohols to form
Imines, Tertiary Amines and Quinolines. Chem. Eur. J. 2019, 25, 6439–6446. [CrossRef] [PubMed]
Sample Availability: Samples of the final products are available from the authors.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).