Visible light induced regioselective C5 halogenation of 8-aminoquinolines with 1,3-dihalo-5,5-dimethylhydantoin in continuous flow

Article abstract of DOI:10.1016/j.tet.2019.05.037

An efficient and convenient method for remote C5 halogenation of 8-aminoquinoline derivatives was developed in continuous flow at room temperature. This method employed inexpensive 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) and 1,3-dichlro-5,5-dimethylhyda

Full text of DOI:10.1016/j.tet.2019.05.037

Accepted Manuscript
Visible light induced regioselective C5 halogenation of 8-aminoquinolines with 1,3-
dihalo-5,5-dimethylhydantoin in continuous flow
Quan Shu, Yaming Li, Tong Liu, Siyu Zhang, Linlin Jiang, Kun Jin, Rong Zhang,
Chunying Duan
PII:
S0040-4020(19)30588-5
https://doi.org/10.1016/j.tet.2019.05.037
TET 30358
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 March 2019
Revised Date: 14 May 2019
Accepted Date: 17 May 2019
Please cite this article as: Shu Q, Li Y, Liu T, Zhang S, Jiang L, Jin K, Zhang R, Duan C, Visible light
induced regioselective C5 halogenation of 8-aminoquinolines with 1,3-dihalo-5,5-dimethylhydantoin in
continuous flow, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.05.037.
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Visible light induced regioselective C5
halogenation of 8-aminoquinolines with 1,3-
dihalo-5,5-dimethylhydantoin in continuous
flow
Leave this area blank for abstract info.
Quan Shu, Yaming Li , Tong Liu, Siyu Zhang, Linlin Jiang, Kun Jin, Rong Zhang and Chunying Duan
State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, Liaoning, P.R. China

1
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Tetrahedron
journal homepage: www.elsevier.com
Visible light induced regioselective C5 halogenation of 8-aminoquinolines with 1,3-dihalo-5,5-
dimethylhydantoin in continuous flow
Quan Shu, Yaming Li , Tong Liu, Siyu Zhang, Linlin Jiang, Kun Jin, Rong Zhang and Chunying Duan
State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, Liaoning, P.R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and convenient method for remote C5 halogenation of 8-aminoquinoline derivatives
was developed in continuous flow at room temperature. This method employed inexpensive 1,3-
dibromo-5,5-dimethylhydantoin (DBDMH) and 1,3-dichlro-5,5-dimethylhydantoin (DCDMH)
as halogenation reagents and visible light to catalyze the reaction. The reaction is scalable to
gram-scale and proceeded with air and moisture tolerance, good functional group compatibility,
and outstanding site selectivity, providing a new pathway for C5 halogenation of 8-
aminoquinolines.
Available online
Keywords:
Visible light induced
Quinoline amide
Halogenation
2009 Elsevier Ltd. All rights reserved
.
Continuous flow
Regioselectivity
1. Introduction
NH2
Quinoline is one of the most privileged structural motifs
because of its existence in many natural products[1], drugs[2], and
pesticides[3]. There have been a large number of reports on
quinolines not only as pharmaceuticals[4], but also as a ligand for
various organic synthesis[5]. Moreover, some reports suggested
the therapeutic effects of quinoline-based derivatives[6]. In recent
years, halogenated quinolines have been constantly found in
many natural products and bioactive molecules, which can be
used as intermediates in the synthesis of substituted quinolines.
Therefore, halogenation of quinolines, especially halogenation at
the C5 position, has been becoming an intensive research focus
on synthetic chemistry[7]. Some important bioactive molecules
with halogenated quinoline unit are shown in Fig 1[8].
Cl
Cl
O
Cl
S
N
O
S
HN
S
Cl
H2N
Ph
N
N
H
N
O
O
O
HO
F
N
NH2
Antimyloidogenic agents
Ammosamide A
KDM4 inhibitot
O
O
OH
I
N
O
N
H
N
S
O
O
O
OH
N
Br
CH3
Ubiquitination inhibitor
Topoisomersa I inhibitor
In 2013, Stahl and co-workers firstly reported Cu(I) catalyzed
C5 chlorination of 8-aminoquinoline using LiCl as chlorination
reagent and molecular O2 as an oxidant[9]. Following this work,
tremendous interest focused on C5 functionalization of 8-
aminoquinolines. The first example of transition-metal-free C5
halogenation of 8-aminoquinoline with NaX (X=Cl, Br) was
reported by Li[10]. However, a certain amount of oxone and
excess loading of NaX were used in this method. Meanwhile, Wu
developed a protocol of transition-metal coupling photoredox
catalyst catalyzed C5 halogenation[11]. In 2018, S. C. Ghosh[12]
disclosed C5 halogenation by heterogeneous Cu-MnO under
Figure 1. Representative natural products and bioactive molecules.
visible light irradiation in which NXS(X= Cl, Br, I) were of
halogen source. Nevertheless, in most cases, the reaction
employed transition-metal and/or oxidant (or additives), which
makes the reactions uneconomical and environmentally
unfriendly, limiting the practicality for large-scale use. The
reactions also involved unfavorable stoichiometric amounts of
the halogen source and high temperature. Therefore new method
with high regioselectivity by using green reagent under the mild
conditions is still thirsted.
———
Corresponding author. Tel/fax: +86 411 84986295.
Corresponding author.
Email: ymli@dlut.edu.cn (Y. Li); cyduan@dlut.edu.cn (C. Duan).

2
Tetrahedron
Visible-light catalyzed reactions[13] and continuous flow
yield of 90% (Table 1, entries 9, 10). Keeping the residence time
ACCEPTED MANUSCRIPT
reactions[14] have captured much attention of academia because of
their safety and sustainability. Studies have showed that
economic savings can be reached in some cases through
transforming batch reaction into a continuous process. Kappe [15]
at 30 min at a flow rate of 53 µL·min-1, and increasing the
Table 1
Optimization of the bromination reaction conditionsa,c
reported
a scalable procedure for light-induced benzylic
Br
O
O
O
brominations showing the advantages of continuous flow. Herein,
we report a mild and environmental-friendly method for visible
light induced halogenation of 8-aminoquinolines by using easy-
available 1,3-dibromo-5,5-dimethylhydantoin (DBDMH)/1,3-
dibromo-5,5-dimethylhydantoin (DCDMH) in continuous flow,
in which outstanding regioselectivity and higher yields were
obtained in a short period of time.
Solvent
N
Br
N
H
N
H
+
N
Blue-LED
Br
N
N
O
1a
2
2a
Entry
Solvent
DBDMH/equiv.
Time/min
Yieldc/%
1
2
3
4
5
1,4-dioxane
THF
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.55
0.6
0.55
0.55
240
240
240
240
240
240
240
240
30
50
30
30
20
11
9
CH3OH
DMF
92
18
94
95
45
95
90
90
94
92
76
92
Previous work
Cl
O
20 mol% CuCl
O
N
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Stahl, 2013
Li, 2016
1 atm O2, 2 eq LiCl
N
H
H
N
N
AcOH, 100
ꢀ, 17 h
6
7d
8e
X
O
O
Oxone (1.5 eq)
DCE, rt, 10 h
+
NaX
R1
N
R1
N
H
9b
10b
11b
12b
13b
14b
H
(4 eq)
N
N
R2
R2
5 mol% alizarin red S
15 mol% FeCl3
X
O
O
O
2 eq K2S2O8, 2 eq KX
Wu, 2017
R
R
N
H
R
N
H2O, household light
15 h, rt
H
N
N
40
aConditions: 1a, (0.2 mmol), solvent (2 mL) at r.t. under irradiation of 15
X
O
Cu-MnO, Air, hv
CH3CN, 2 h
b
Ghosh, 2018
NXS
+
W blue-LED in a batch in air. 1a, (0.2 mmol), solvent (2 mL) at r.t. under
R
N
H
N
H
irradiation of 15 W blue LED in continuous flow in air. cGC yield. dDark. eAr
atmosphere.
(X=Cl, Br, I)
N
N
Household CFL
Br
R
R
Kappe, 2014
NBS
+
amount of DBDMH to 0.55 equivalent, the yield of 2a reached
up to 94% (Table 1, entry 11). Further increasing the loading of
DBDMH, however, the yield of brominated product just remains
unchanged (Table 1, entry 12). Either prolonged or shorten
resident time did not lead to the higher yield (Table 1, entries 13-
14). Thus optimized reaction conditions in continuous flow were
achieved using 0.55 equivalent of DBDMH in CH2Cl2 at ambient
temperature for 30 min under irradiation of blue-LED in air.
This work
Cl
O
O
450 nm LED
450 nm LED
Br
N
Cl
N Br
N
N
Cl
Br
O
O
N
TBHP, 60 min, rt
CH2Cl2
30 min, rt
CH2Cl2
N
NHR
N
NHR
NHR
Scheme 1. Remote halogenation of quinoline at C5 position.
Having identified the optimal reaction conditions for
bromination of 1a with DBDMH, the substrate scope were then
examined in continuous flow (Table 2). Both the electron-
donating (CH3, OCH3) (2b–2e) and electron-withdrawing (F, Cl)
(2f–2h) substituted benzamides exhibited good reactivity
affording the desired products in good to excellent yields. The
yields of benzamides bearing electron-donating groups are higher
than those bearing electron-withdrawing groups. Moreover, the
alkyl amides could also provide the desired brominated products
in good yields (2i-2l). Furthermore, the heteroaromatic amide
was also compatible in this process and delivered corresponding
product in good yield (2m). Surprisingly, 1n, which is not easy to
halogenate under metal catalyst[8][16] or transition metal free
conditions[7c][17], served well under the optimal conditions (2n).
This methodology was successfully applied to sulfonamide
giving the target products in moderate to good yields (2o-2q).
2. Results and discussion
Initially, the bromination of N-8-quinolinyl-benzamide (1a)
with DBDMH (2) was selected as a model to screen the reaction
parameters in batch. When the reaction was carried out at room
temperature for 4 h under irradiation of blue-LED using 1,4-
dioxane as solvent, only 11% yield of C5 brominated product
(2a) was obtained (Table 1, entry 1). Solvents were screened
firstly since solvent plays an important role in photo-induced
reactions. Either tetrahydrofuran (THF) or N, N-dimethyl
formamide (DMF) used as the solvent, resulted in poor remote
C5-brominated conversions (Table 1, entries 2, 4). Other solvents
such as methanol (CH3OH), acetonitrile (CH3CN), and
dichloromethane (CH2Cl2), however, gave the desired product 2a
in excellent yields of 92-95% (Table 1, entries 3, 5, 6).
Considering of the poor solubility of 2a in CH3OH and CH3CN,
the CH2Cl2 was selected as solvent in the following reactions. For
the control experiments, the reactions were carried out in the dark
and the yield of 2a was drastically reduced to 45% (Table 1,
entry 7), and with Ar instead of open-air atmosphere there was no
significant improvement of the 2a yield. Transitioning to
continuous flow using CH2Cl2 as solvent, the residence time and
the amount of DBDMH were tested. To our delight, even within
30 minutes of residence time in flow, the reaction went to end
and the C5-brominated product 2a was obtained in a satisfactory
Gram-scale up reaction
One of the advantages of the continuous flow system is that
the reaction can be scaled up easily in contrast with batch, where
a larger scale requires a corresponding new reactor. To
demonstrate the utility of the protocol, N-8-quinolinyl-benzamide
(5 mmol, 1.240 g) was used under the optimized reaction
conditions at 53.3 µL·min-1 flow rate in continuous flow where

3
the desired product 2a was obtained in 85% yield (1.390 g) after
purification on silica gel.
reaction was also amenable to heteroaromatic amide (3f) and
alkyl amides (3g-i), giving the target products in good yields.
ACCEPTED MANUSCRIPT
Table 2
Table 3
Substrate scope of the C5 bromination of quinolinesa,b
Optimization of the chlorination reaction conditionsa,d
450 nm LED
Br
Cl
O
O
O
O
Time
TBHP
N
Cl
N
H
N
H
+
N
+
N
Br
DCM Blue LED
Cl
N
N
N
N
N
O
Br
2 (0.55 equiv)
Br
1a
3
3a
NHR
2a-q
NHR
1a-q
O
Entry Solvent
DCDMH/equiv
0.55
1.1
TBHP/equiv
2.1
Time/h
4
4
4
4
8
8
8
8
12
12
12
12
12
0.5
1
1.5
4
12
YieldC/%
13
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Br
Br
Br
Br
O
O
O
2.1
3.5
3.5
2.1
2.1
3.5
3.5
2.1
2.1
3.5
3.5
3.5
3.5
3.5
3.5
18
27
48
19
51
44
65
25
55
50
97
42
55
92
90
Trace
35
N
N
N
3
4
5
6
7
8
9
0.55
1.1
0.55
1.1
0.55
1.1
0.55
1.1
0.55
1.1
1.1
1.1
1.1
H
H
H
N
N
N
N
2a 90%
2b 92%
2c 90%
Br
O
O
O
N
H
N
H
N
H
N
N
H3CO
F
2f 81%
2e 84%
2d 93%
10
11
12
13c
14b
15b
16b
17
18
Br
Br
Br
Br
O
Cl
O
O
N
N
H
N
H
H
N
N
N
Cl
2i 82%
2h 87%
2g 91%
1.1
0.55
1.1
Br
Br
Br
Br
O
O
O
N
H
N
H
N
H
N
N
N
N
aConditions: 1a, (0.2 mmol), TBHP 70 % in water, solvent (2 mL) under
2j 85%
2k 87%
2l 83%
b
irradiation of 15 W blue-LED at r.t. in a batch in air. 1a, (0.2 mmol), TBHP
Br
O
O
O
O
(70 % in water), solvent (2 mL) under irradiation of 15 W blue LED at room
temperature in continuous flow in air. cDark. dGC yields.
S
N
N
N
H
H
N
S
N
2m 86%
2n 84%
2o 87%
Br
Br
O
O
O
O
Table 4
S
S
N
H
N
H
Substrate scope of the C5 chlorination of quinolinesa,b
S
N
N
2q 55%
2p 79%
450 nm LED
Cl
O
aConditions: Substituted quinolines (0.2 mmol), DBDMH (0.55 equiv.), DCM
(2 mL) under irradiation of 15 W blue-LED in continuous flow for 30 min in
air. bIsolated yields on silica gel column chromatography.
(3.5 equiv)
TBHP
N
Cl
+
N
N
N
Cl
O
NHR
3a-i
NHR
3 (1.1 equiv)
1a-i
Cl
Cl
Cl
O
O
O
C5 chlorination of 8-aminoquinolines
N
N
N
H
H
H
N
N
N
F
H3CO
Cl
Encouraged by the good results of bromination reaction, this
reaction system was applied to the corresponding chlorination of
8-aminoquinoline derivatives using DCDMH (3). Unfortunately,
trace C5 chlorination product was detected (Table 3, Entry 17).
However, adding 2.1 equivalents of tert-butyl hydroperoxide
(TBHP), 13% yield of 3a quinoline chlorination at the C5
position was observed. Then the reaction conditions were further
optimized as follows: 1.1 equivalent of DCDMH and 3.5
equivalent of TBHP under irradiation of blue-LED in continuous
flow for 1 h in air (Table 3, entry 15).
3c 80%
3a 91%
3b 87%
Cl
Cl
Cl
O
O
Cl
O
N
H
N
H
N
H
S
N
N
N
N
Cl
3e 86%
3f 89%
3d 75%
Cl
Cl
O
O
O
N
H
N
H
N
H
N
N
3g 80%
3h 85%
3i 84%
aConditions: Substituted quinolines (0.2 mmol), DCDMH (1.1 equiv.), TBHP
(70 % in water, 3.5 equiv.), DCM (2 mL) under irradiation of 15 W blue-LED
in continuous flow for 1 h in air. bIsolated yields on silica gel column
chromatography.
With the optimized reaction conditions in hand, we set out to
investigate the applicability of the present protocol for the scope
of acyl motif. A broad range of quinoline substrates readily
participated in this mild chlorination with great efficiency (Table
4). Both electron-donating (3b) and electron-withdrawing (3c-3e)
benzamides were well tolerated in the current reaction system
and the desired products were obtained in good to excellent
yields. The reactants with electron-donating substituents afforded
the desired products in higher yields relative to those with
electron-withdrawing groups. In addition to good tolerance of
different kinds of carboxamide with aromatic substitutions, this
Mechanism studies
To gain more insight into the reaction mechanism, radical
capturing experiments were put into effect. When 2.0 equivalents
of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) were added

4
Tetrahedron
ACCEPTED MANUSCRIPT
1
into either bromination or chlorination reaction system, the
CDCl3 (δ = 7.26 for H and δ = 77.16 for 13C NMR) as internal
standard. GC chromatography with FID detector from Agilent
and GC-MS from Thermo were used to record data. High-
resolution mass spectrometry data were also recorded in the ESI-
TOF.
yield of the desired product decreased sharply to 15% and 13%
respectively, implying that the reaction follows a radical pathway.
Based on our experiment and the previous work[17,18], possible
reaction mechanism was outlined in Scheme 2. Initially, the
active bromine and complex A radical species were created from
DBDMH under blue-LED irradiation. In following propagation
process, Br radical or A radical react with stable molecules 1a to
form radical intermediate C and HBr or complex F. Next, C
could tautomerize to stable intermediates D and E. Br2 was
generated through combining of HBr and complex A, which then
underwent a bromination process with intermediate C or E to
give the C5 brominated product 2a. Beside this process, 2a could
also be obtained through bromine radical and intermediates C or
E.
4.2. General procedure for synthesis of starting amides
The synthesis of starting amides was according to previously
reported literature[19]. 5 mmol of 8-aminoquinoline, and 6 mmol
of triethylamine were dissolved in 20 mL of CH2Cl2, stirred in
100 mL single neck flask at room temperature for 5 minutes, the
reaction solution was cooled in an ice bath afterwards. The acid
chloride (6 mmol) was added dropwise (if the acid chloride is
solid, it was dissolved with 5 mL CH2Cl2). The reaction solution
was allowed to stir overnight at room temperature. The reaction
mixture was washed with CH2Cl2, and the organic layer with 1M
NaHCO3 (3×15 mL). The organic layer was dried over anhydrous
Na2SO4, subsequently. The solvent was removed over rotary
evaporator. The product was purified by silica gel column
chromatography with PE/EtOAc (10 : 1).
TBHP could liberate tert-butoxy radical (t-BuO·) under blue-
LED irradiation which may promote the formation of chlorine
radical or intermediates C-E. The following chlorination
procedure is similar to the bromination process.
Br
H
N
N
4.3. General procedure for synthesis of N-methyl-N-
(quinolin-8-yl)benzamide
O
O
N
O
N
O
Br
Br
H
2
B
N
O
N
O
The synthesis of N-methyl-N-(quinolin-8-yl)benzamide was
according to previously reported literature[20]. To a suspension of
sodium hydride (2.0 mmol) in 5 mL of dry dimethylformamide,
was added a solution of N-8-quinolinyl-benzamide (1.0 mmol) in
5 mL of dry dimethylformamide in an ice bath. The reaction was
warmed to room temperature and stirred for another hour. Methyl
iodide (1.0 mmol) was added and the reaction mixture was stirred
for a further half hour, subsequently. Then the reaction mixture
was washed with 30 mL of CH2Cl2 and the organic layer was
washed with water (3×15 mL). The organic layer was dried over
anhydrous Na2SO4, and the solvent removed roto-evaporated.
The product was purified by column chromatography using
CH2Cl2 as eluent.
A
hv
Br2
HBr
Br
Br
Br
H
O
O
O
O
O
N
H
N
N
H
N
H
N
N
N
N
2a
E
C
1a
Br
Br
Br
N
N
H
O
O
N
N
O
O
N
H
F
A
N
D
Scheme 2. Proposed mechanism for the bromination of quinolines
3. Conclusion
4.4. General procedure for the synthesis of brominated
quinolines in continuous flow
In summary, an efficient visible-light induced, C5
halogenation of 8-aminoquinolines in continuous flow was
developed, in which, a smaller amount of low-cost and easy
available DBDMH and DCDMH were used as halogenation
reagents. The reaction condition of chlorination differs from that
of bromination due to the less reactivity of DCDMH. Both
chlorination and bromination reaction reveals good functional
group tolerance and high reactivity (short reaction time and high
yields) under open-air conditions. Gram-scale of the desired
product can easily be obtained simply in continuous flow.
0.2 mmol of substituted quinolines and 0.11 mmol of
DBDMH in CH2Cl2 (2 mL) was injected into the pump, then the
reaction mixture entered into the fluorinated ethylene propylene
(FEP) tubing convection flow coil reactor (1/32 inner diameter,
1.6 ml inner volume, 53.3 µL·min-1 flow rate), which was
maintained at room temperature (residence time = 30 min) and
under the irradiation of blue-LED. The reaction mixture was
collected at a test tube and then concentrated under vacuum. The
residue was purified by column chromatography on silica gel
(200-300 mesh) with PE/EtOAc (10 : 1) to give the final products.
4.4.1. N-(5-bromoquinolin-8-yl)benzamide (2a):
4. Experiment
Obtained as a white solid in 90%; 1H NMR (500 MHz,
CDCl3) δ 10.54 (s, 1H), 8.71 (dd, J = 5.0, 3.4 Hz, 2H), 8.35 (dd, J
= 8.5, 1.6 Hz, 1H), 8.00 (dd, J = 5.2, 3.3 Hz, 2H), 7.69 (d, J = 8.4
4.1. General information
All the chemicals unless otherwise noted, were obtained
commercially and used without further purification. All products
were isolated by column chromatography on a silica gel (200-300
mesh). Continuous flow reactor from Syrris Ltd and Corning
were used for the continuous flow process. 1H NMR spectra were
determined on Bruker instruments with operating frequencies of
400 or 500 MHz spectrometer as solutions in CDCl3. Chemical
shifts were expressed in parts per million (δ) and the signals were
reported as s (singlet), d (doublet), dd (doublet of doublet), t
(triplet), m (multiplet), and coupling constants (J) were given in
Hz. 13C NMR spectra were recorded at 101 or 125 MHz in CDCl3
solution. Chemical shifts as internal standard were referenced to
Hz, 1H), 7.56-7.45 (m, 3H), 7.42 (dd, J = 8.5, 4.2 Hz, 1H). 13
NMR (126 MHz, CDCl3) δ 165.13 , 148.67, 139.19 , 135.79 ,
134.71 , 134.36 , 131.99 , 130.81 , 128.82 , 127.24 , 127.04 ,
122.65 , 116.85 , 114.36. GC-MS (EI, m/z): 328 (M+).
C
4.4.2. N-(5-bromoquinolin-8-yl)-2-
methylbenzamide (2b):
Obtained as a white solid in 92%; 1H NMR (400 MHz, CDCl3)
δ 10.19 (s, 1H), 8.84 (d, J = 8.4 Hz, 1H), 8.79 (dd, J = 4.2, 1.6 Hz,
1H), 8.54 (dd, J = 8.5, 1.5 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.67
(d, J = 7.7 Hz, 1H), 7.55 (dt, J = 7.5, 3.7 Hz, 1H), 7.44 – 7.38 (m,
1H), 7.32 (t, J = 7.6 Hz, 2H), 2.60 (s, 3H). 13C NMR (101 MHz,

5
CDCl3) δ 168.14, 148.77, 139.32, 136.82, 136.33, 136.02, 134.67,
130.20, 127.23, 127.21, 122.77, 117.37, 114.92. GC-MS (EI,
m/z): 362 (M+).
ACCEPTED MANUSCRIPT
131.48, 130.96, 130.52, 127.26, 126.08, 122.74, 117.02, 114.51,
20.25. HRMS (ESI) m/z: [M+H]+ Calcd For C17H14BrN2O
343.0191; found 343.0292.
4.4.9. N-(5-bromoquinolin-8-yl)acetamide (2i):
Obtained as a white solid in 82%; 1H NMR (500 MHz,
CDCl3) δ 9.71 (s, 1H), 8.76 (dd, J = 4.1, 1.6 Hz, 1H), 8.61 (d, J =
8.4 Hz, 1H), 8.45 (dd, J = 8.5, 1.6 Hz, 1H), 7.73 (d, J = 8.4 Hz,
1H), 7.51 (dd, J = 8.5, 4.2 Hz, 1H), 2.34 (s, 3H). 13C NMR (126
MHz, CDCl3) δ 168.60, 148.52, 138.80, 135.87, 134.38, 130.83,
127.04, 122.59, 116.81, 114.06, 25.14. GC-MS (EI, m/z):266
(M+).
4.4.3. N-(5-bromoquinolin-8-yl)-3-
methylbenzamide (2c):
Obtained as a white solid in 90%; 1H NMR (400 MHz, CDCl3)
δ 10.64 (s, 1H), 8.84 (d, J = 4.1 Hz, 1H), 8.81 (d, J = 8.4 Hz, 1H),
8.51 (d, J = 8.5 Hz, 1H), 7.83 (dd, J = 14.0, 7.1 Hz, 3H), 7.55 (dd,
J = 8.5, 4.2 Hz, 1H), 7.45 – 7.36 (m, 2H), 2.47 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 165.61, 148.76, 139.42, 138.75, 135.99,
134.85, 134.57, 132.80, 130.98, 128.70, 128.06, 127.23, 124.21,
122.72, 117.02, 114.35, 21.51. HRMS (ESI) m/z: [M+H]+ Calcd
For C17H14BrN2O 343.0191; found 343.0295.
4.4.10. N-(5-bromoquinolin-8-yl)pivalamide (2j):
Obtained as a white solid in 85%; 1H NMR (500 MHz,
CDCl3) δ 10.21 (s, 1H), 8.80 (d, J = 2.9 Hz, 1H), 8.68 (d, J = 8.4
Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.52
(dd, J = 8.4, 4.1 Hz, 1H), 1.42 (s, 9H). 13C NMR (126 MHz,
CDCl3) δ 177.22, 148.66, 139.42, 135.85, 134.62, 130.89,
127.10, 122.55, 116.69, 113.86, 40.38, 27.69. HRMS (ESI) m/z:
[M+H]+ Calcd For C14H15BrN2ONa 329.0368; found 329.0266.
4.4.4. N-(5-bromoquinolin-8-yl)-4-
methylbenzamide (2d):
Obtained as a white solid in 93%; 1H NMR (500 MHz, CDCl3)
δ 10.58 (s, 1H), 8.77 (dd, J = 4.1, 1.3 Hz, 1H), 8.74 (d, J = 8.4 Hz,
1H), 8.44 (dd, J = 8.5, 1.3 Hz, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.75
(d, J = 8.4 Hz, 1H), 7.49 (dd, J = 8.5, 4.2 Hz, 1H), 7.26 (d, J =
7.9 Hz, 2H), 2.37(s, 3H). 13C NMR (126 MHz, CDCl3) δ 164.34,
147.68, 141.53, 138.41, 134.96, 133.60, 131.01, 129.96, 128.47,
126.26, 121.66, 115.92, 113.19, 20.53. HRMS (ESI) m/z:
[M+H]+ Calcd For C17H14BrN2O 343.0191; found 343.0279.
4.4.11. N-(5-bromoquinolin-8-yl)butyramide (2k):
Obtained as a white solid in 87%; 1H NMR (500 MHz, CDCl3)
δ 9.66 (s, 1H), 8.69 (d, J = 3.6 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H),
8.38 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.43 (dd, J =
8.4, 4.1 Hz, 1H), 2.45 (t, J = 7.5 Hz, 2H), 1.81 – 1.71 (m, 2H),
0.97 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 171.70,
148.54, 138.96, 135.87, 134.45, 130.89, 127.09, 122.57, 116.83,
113.93, 40.12, 19.04, 13.81. HRMS (ESI) m/z: [M+H]+ Calcd
For C13H14BrN2O 293.0211; found 293.0446.
4.4.5. N-(5-bromoquinolin-8-yl)-4-
methoxybenzamide (2e):
Obtained as a white solid in 84%; 1H NMR (500 MHz, CDCl3)
δ 10.65 (s, 1H), 8.88 (dd, J = 4.2, 1.5 Hz, 1H), 8.83 (d, J = 8.4 Hz,
1H), 8.56 (dd, J = 8.5, 1.5 Hz, 1H), 8.07 – 8.03 (m, 2H), 7.85 (d,
J = 8.4 Hz, 1H), 7.60 (dd, J = 8.5, 4.2 Hz, 1H), 7.07 – 7.02 (m,
2H), 3.90 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 164.93, 162.67,
148.67, 139.43, 136.01, 134.71, 131.02, 129.19, 127.25, 127.14,
122.68, 116.87, 114.05, 55.48. GC-MS (EI, m/z): 358 (M+).
4.4.12. N-(5-bromoquinolin-8-yl)-2-
phenylacetamide (2l):
Obtained as a white solid in 83%; 1H NMR (500 MHz,
CDCl3) δ 9.82 (s, 1H), 8.62 (dd, J = 11.3, 6.1 Hz, 2H), 8.39 (d, J
= 8.4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.45 – 7.37 (m, 5H), 7.33
(t, J = 6.7 Hz, 1H), 3.86 (s, 2H). 13C NMR (126 MHz, CDCl3) δ
169.49, 148.60, 139.03, 135.75, 134.48, 134.27, 130.78, 129.56,
129.04, 127.45, 127.02, 122.55, 116.77, 114.27, 45.36. HRMS
(ESI) m/z: [M+H]+ Calcd For C17H14BrN2O 343.0191; found
343.0454.
4.4.6. N-(5-bromoquinolin-8-yl)-4-
fluorobenzamide (2f):
Obtained as a white solid in 81%; 1H NMR (500 MHz, CDCl3)
δ 10.64 (s, 1H), 8.86 (dd, J = 4.2, 1.5 Hz, 1H), 8.79 (d, J = 8.4 Hz,
1H), 8.54 (dd, J = 8.5, 1.5 Hz, 1H), 8.11 – 8.04 (m, 2H), 7.83 (d,
J = 8.4 Hz, 1H), 7.59 (dd, J = 8.5, 4.2 Hz, 1H), 7.25 – 7.19 (m,
2H). 13C NMR (126 MHz, CDCl3) δ 166.10 (d, JCF = 252.9 Hz),
164.26, 148.78, 139.35, 136.12, 134.34, 131.04(d, JCF = 3.1 Hz),
130.98, 129.72(d, JCF = 9.1 Hz), 127.28, 122.78, 117.06 ꢁ
116.02(d, JCF = 22.0 Hz), 114.56. GC-MS (EI, m/z): 346 (M+).
4.4.13. N-(5-bromoquinolin-8-yl)thiophene-2-
carboxamide (2m):
Obtained as a white solid in 86%; 1H NMR (500 MHz, CDCl3)
δ 10.47 (s, 1H), 8.79 (dd, J = 4.2, 1.4 Hz, 1H), 8.66 (d, J = 8.4 Hz,
1H), 8.46 (dd, J = 8.5, 1.4 Hz, 1H), 7.77 – 7.73 (m, 2H), 7.56 –
7.48 (m, 2H), 7.14 – 7.09 (m, 1H). 13C NMR (126 MHz, CDCl3)
δ 159.95, 148.80, 139.78, 139.19, 136.03, 134.27, 131.16, 130.99,
128.59, 127.91, 127.27, 122.77, 116.99, 114.43. HRMS (ESI)
m/z: [M-H]- Calcd For C14H8BrN2OS 332.9598; found 332.9536.
4.4.7. N-(5-bromoquinolin-8-yl)-4-
chlorobenzamide (2g):
Obtained as a white solid in 91%; 1H NMR (500 MHz,
CDCl3) δ 10.64 (s, 1H), 8.85 (dd, J = 4.2, 1.4 Hz, 1H), 8.77 (d, J
= 8.4 Hz, 1H), 8.53 (dd, J = 8.5, 1.4 Hz, 1H), 7.99 (d, J = 8.5 Hz,
2H), 7.82 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 8.5, 4.2 Hz, 1H), 7.51
(d, J = 8.5 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 164.18 ,
148.81 , 139.31 , 138.34 , 136.05 , 134.22 , 133.17 , 130.93 ,
129.11 , 128.69 , 127.23 , 122.79 , 117.04 , 114.66. GC-MS (EI,
m/z): 362 (M+).
4.4.14. N-(5-bromoquinolin-8-yl)-N-
methylbenzamide (2n):
Obtained as a white solid in 84%; 1H NMR (500 MHz,
CDCl3) δ 8.99 (dd, J = 4.1, 1.5 Hz, 1H), 8.47 (dd, J = 8.5, 1.5 Hz,
1H), 7.65 (d, J = 8.0 Hz, 1H), 7.52 (dd, J = 8.5, 4.1 Hz, 1H), 7.29
(dd, J = 7.7, 3.0 Hz, 3H), 7.11 (t, J = 7.4 Hz, 1H), 7.01 (t, J = 7.6
Hz, 2H), 3.57 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.04,
151.11, 144.54, 142.52, 136.53, 135.82, 129.96, 129.47, 129.28,
128.49, 127.92, 127.53, 122.80, 120.98, 38.59. HRMS (ESI) m/z:
[M+H]+ Calcd For C17H14BrN2O 343.0191; found 343.0261.
4.4.8. N-(5-bromoquinolin-8-yl)-2-
chlorobenzamide (2h):
Obtained as a white solid in 87%; 1H NMR (500 MHz, CDCl3)
δ 10.50 (s, 1H), 8.88 – 8.79 (m, 2H), 8.54 (d, J = 8.5 Hz, 1H),
7.86 (d, J = 8.4 Hz, 1H), 7.82 (dd, J = 7.4, 1.7 Hz, 1H), 7.57 (dd,
J = 8.5, 4.2 Hz, 1H), 7.52 – 7.49 (m, 1H), 7.43 (tdd, J = 14.9,
10.5, 4.5 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 164.79, 148.87,
139.30, 135.93, 135.48, 134.36, 131.70, 131.16, 130.88, 130.58,
4.4.15. N-(5-bromoquinolin-8-yl)-4-
methylbenzenesulfonamide (2o):
Obtained as a white solid in 87%; 1H NMR (500 MHz, CDCl3)
δ 9.12 (s, 1H), 8.69 (dd, J = 4.2, 1.5 Hz, 1H), 8.35 (dd, J = 8.5,
1.5 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 2.3 Hz, 2H),

6
Tetrahedron
ACCEPTED MANUSCRIPT
7.44 (dd, J = 8.5, 4.2 Hz, 1H), 7.09 (d, J = 8.1 Hz, 2H), 2.22 (s,
= 8.4 Hz, 1H), 8.47 (dd, J = 8.5, 1.3 Hz, 1H), 8.00 – 7.93 (m,
3H). 13C NMR (126 MHz, CDCl3) δ 149.19, 143.99, 139.10,
136.22, 135.89, 133.85, 130.35, 129.63, 127.49, 127.23, 123.02,
115.24, 114.88, 21.47. HRMS (ESI) m/z: [M-H]- Calcd For
C16H12BrN2O2S 376.9861; found 376.9792.
2H), 7.53 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 8.5, 4.2 Hz, 1H), 7.12
(t, J = 8.5 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 166.08(d, JCF
= 252.9 Hz), 164.18, 148.76, 139.21, 134.65, 133.69, 133.46,
131.04(d, JCF = 3.1 Hz), 129.69(d, JCF = 9.0 Hz), 127.26, 125.97,
124.58, 116.42, 115.99(d, JCF = 21.9 Hz). HRMS (ESI) m/z:
[M+Na]+ Calcd For C16H10ClFN2ONa 325.0334; found 325.0331.
4.4.16. N-(5-bromoquinolin-8-yl)-1-
phenylmethanesulfonamide (2p):
Obtained as a white solid in 79%; 1H NMR (500 MHz, CDCl3)
δ 8.83 (s, 1H), 8.70 (dd, J = 4.2, 1.4 Hz, 1H), 8.48 (dd, J = 8.5,
1.4 Hz, 1H), 7.68 (t, J = 9.9 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H),
7.55 (dd, J = 8.5, 4.2 Hz, 1H), 7.24 (t, J = 5.4 Hz, 1H), 7.13 (t, J
= 7.6 Hz, 2H), 7.08 (d, J = 7.5 Hz, 2H), 4.39 (s, 2H). 13C NMR
(126 MHz, CDCl3) δ 149.15, 138.71, 135.95, 134.33, 130.72,
130.46, 128.81, 128.66, 128.12, 127.53, 123.18, 114.97, 114.86,
58.04. HRMS (ESI) m/z: [M-H]- Calcd For C16H12BrN2O2S
376.9861; found 376.9795.
4.5.4. 4-chloro-N-(5-chloroquinolin-8-
yl)benzamide (3d):
Obtained as a white solid in 75%; 1H NMR (500 MHz,
CDCl3) δ 10.51 (s, 1H), 8.79 – 8.75 (m, 1H), 8.72 (d, J = 8.4 Hz,
1H), 8.48 – 8.44 (m, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.52 (d, J =
8.4 Hz, 1H), 7.48 (dd, J = 8.5, 4.2 Hz, 1H), 7.41 (d, J = 8.4 Hz,
2H). 13C NMR (126 MHz, CDCl3) δ 164.16, 148.79, 139.19,
138.31, 133.58, 133.47, 133.19, 129.09, 128.67, 127.25, 125.97,
124.70, 122.44, 116.48. HRMS (ESI) m/z: [M+Na]+ Calcd For
C16H10Cl2N2ONa 341.0039; found 341.0033.
4.4.17. N-(5-bromoquinolin-8-yl)thiophene-2-
sulfonamide (2q):
4.5.5. 2-chloro-N-(5-chloroquinolin-8-
yl)benzamide (3e):
Obtained as a white solid in 55%; 1H NMR (500 MHz,
CDCl3) δ 9.21 (s, 1H), 8.71 (d, J = 3.9 Hz, 1H), 8.40 (d, J = 8.5
Hz, 1H), 7.71 (dd, J = 20.2, 8.3 Hz, 2H), 7.59 – 7.54 (m, 1H),
7.47 (dd, J = 8.5, 4.2 Hz, 1H), 7.38 (d, J = 4.9 Hz, 1H), 6.87 (t, J
= 4.4 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 149.32, 139.60,
139.26, 135.97, 133.47, 132.84, 132.42, 130.36, 127.54, 127.19,
123.11, 115.81, 115.50. HRMS (ESI) m/z: [M-H]- Calcd For
C13H8BrN2O2S2 368.9268; found 368.9196.
Obtained as a white solid in 86%; 1H NMR (500 MHz,
CDCl3) δ 10.48 (s, 1H), 8.90 (d, J = 8.4 Hz, 1H), 8.84 (dd, J =
4.2, 1.5 Hz, 1H), 8.59 (dd, J = 8.5, 1.5 Hz, 1H), 7.82 (dd, J = 7.4,
1.9 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 8.5, 4.2 Hz,
1H), 7.51 (dd, J = 7.8, 1.3 Hz, 1H), 7.43 (dtd, J = 17.3, 7.4, 1.6
Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 164.82, 148.85, 139.21,
135.53, 133.72, 133.44, 131.69, 131.18, 130.58, 130.20, 127.26,
127.21, 126.02, 124.97, 122.44, 116.89. HRMS (ESI) m/z:
[M+Na]+ Calcd For C16H10Cl2N2ONa 341.0039; found 341.0041.
4.5. General procedure for the synthesis of chlorinated
quinolines in continuous flow
4.5.6. N-(5-chloroquinolin-8-yl)thiophene-2-
carboxamide (3f):
A solution of substituted quinolines (0.2 mmol), DCDMH
(0.22 mmol) and TBHP (70% in water, 0.7 mmol) in DCM (2
mL) was injected into the pump, then the reaction mixture
entered into the fluorinated ethylene propylene (FEP) convection
flow coil reactor (1/32 inner diameter, 1.6 ml inner volume, 26.7
µL·min-1 flow rate), which was maintained at room temperature
(residence time = 60 min) and under the irradiation of blue-LED.
The reaction mixture was collected at a test tube and then
concentrated under vacuum. The residue was purified by column
chromatography on silica gel (200-300 mesh) with PE/EtOAc to
give the final products.
Obtained as a white solid in 89%; 1H NMR (500 MHz,
CDCl3) δ 10.58 – 10.45 (s, 1H), 8.87 (dd, J = 4.2, 1.5 Hz, 1H),
8.76 (d, J = 8.4 Hz, 1H), 8.61 – 8.51 (m, 1H), 7.81 (dd, J = 3.7,
0.8 Hz, 1H), 7.59 (ddd, J = 12.7, 11.0, 6.3 Hz, 3H), 7.18 (dd, J =
4.8, 3.8 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 159.93, 148.78,
139.77, 139.01, 133.59, 133.43, 131.14, 128.56, 127.91, 127.29,
125.97, 124.49, 122.43, 116.39. HRMS (ESI) m/z: [M+Na]+
Calcd For C14H9ClN2OSNa 312.9993; found 312.9988.
4.5.7. N-(5-chloroquinolin-8-yl)pivalamide (3g):
Obtained as a white solid in 80%; 1H NMR (400 MHz,
CDCl3) δ 10.21 (s, 1H), 8.84 (d, J = 4.1 Hz, 1H), 8.74 (d, J = 8.4
Hz, 1H), 8.53 (d, J = 8.5 Hz, 1H), 7.59 – 7.52 (m, 2H), 1.43 (s,
9H). 13C NMR (101 MHz, CDCl3) δ 177.26, 148.68, 139.31,
133.99, 133.33, 127.25, 125.88, 123.96, 122.25, 116.12, 40.37,
27.71. HRMS (ESI) m/z: [M+Na]+ Calcd For C14H15ClN2ONa
285.0873; found 285.0771.
4.5.1. N-(5-chloroquinolin-8-yl)benzamide (3a):
Obtained as a white solid in 91%; 1H NMR (500 MHz,
CDCl3) δ 10.53 (s, 1H), 8.75 (dd, J = 5.0, 3.5 Hz, 2H), 8.42 (dd, J
= 8.5, 1.5 Hz, 1H), 7.97 – 7.92 (m, 2H), 7.53 – 7.41 (m, 5H). 13
C
NMR (126 MHz, CDCl3) δ 164.24, 147.85, 138.17, 133.78,
132.77, 132.31, 130.93, 127.77, 126.38, 126.20, 124.87, 123.38,
121.32, 115.34. HRMS (ESI) m/z: [M+Na]+ Calcd For
C16H11ClN2ONa 307.0428; found 307.0419.
4.5.8. N-(5-chloroquinolin-8-yl)butyramide (3h):
Obtained as a white solid in 85%; 1H NMR (500 MHz,
CDCl3) δ 9.65 (s, 1H), 8.74 – 8.70 (m, 1H), 8.62 (d, J = 8.4 Hz,
1H), 8.43 (d, J = 8.4 Hz, 1H), 7.49 – 7.42 (m, 2H), 2.45 (t, J =
7.5 Hz, 2H), 1.81 – 1.72 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13C
NMR (126 MHz, CDCl3) δ 171.76, 148.52, 138.80, 133.77,
133.33, 127.22, 125.84, 124.04, 122.25, 116.31, 40.10, 19.06,
13.81. HRMS (ESI) m/z: [M+Na]+ Calcd For C13H13ClN2ONa
271.0716; found 271.0743.
4.5.2. N-(5-chloroquinolin-8-yl)-4-
methoxybenzamide (3b):
Obtained as a white solid in 87%; 1H NMR (500 MHz,
CDCl3) δ 10.61 (s, 1H), 8.91 – 8.82 (m, 2H), 8.58 (dd, J = 8.5,
1.5 Hz, 1H), 8.09 – 7.99 (m, 2H), 7.64 (d, J = 8.4 Hz, 1H), 7.58
(dd, J = 8.5, 4.2 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H).
13C NMR (126 MHz, CDCl3) δ 164.94, 162.65, 148.67, 139.31,
134.08, 133.44, 129.18, 127.36, 127.17, 126.00, 124.15, 122.36,
116.28, 114.04, 55.49. HRMS (ESI) m/z: [M+Na]+ Calcd For
C17H13ClN2O2Na 337.0534; found 337.0530.
4.5.9. N-(5-chloroquinolin-8-yl)-2-
phenylacetamide (3i):
Obtained as a white solid in 84%; 1H NMR (500 MHz,
CDCl3) δ 9.81 (s, 1H), 8.66 (d, J = 7.7 Hz, 2H), 8.43 (d, J = 8.5
Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.45 – 7.38 (m, 5H), 7.33 (t, J
= 6.8 Hz, 1H), 3.87 (s, 2H). 13C NMR (126 MHz, CDCl3) δ
169.49, 148.59, 138.89, 134.51, 133.62, 133.19, 129.56, 129.04,
4.5.3. N-(5-chloroquinolin-8-yl)-4-
fluorobenzamide (3c):
Obtained as a white solid in 80%; 1H NMR (500 MHz,
CDCl3) δ 10.50 (s, 1H), 8.77 (dd, J = 4.1, 1.3 Hz, 1H), 8.73 (d, J

7
Huang, W. C. H. Fu, K. C. Hsu, Y. M. Liu, Y. W. Wu, C. F. Lin,
Y. L. Chen, M. J. Lai, H. Y. Lee, J. P. Liou, C. M. Teng, C. R.
Yang, Oncotarget. 2017, 8, 27772–27785.
127.44, 127.11, 125.75, 124.32, 122.22, 116.21, 45.33. HRMS
(ESI) m/z: [M+H]+ Calcd For C17H14ClN2O 297.0716; found
279.0742.
ACCEPTED MANUSCRIPT
7. (a) B. Khan, H. S. Dutta, D. Koley, Asian J. Org. Chem. 2018, 7,
1270 – 1297. (b) T. Iwai, M. Sawamura, ACS Catal. 2015, 5,
5031-5040. (c) J. Xu, X. Zhu, G. Zhou, B. Ying, P. Ye, L. Su, C.
4.6. Procedure for scale-up bromination reaction of N-8-
quinolinyl-benzamide
Shen, P. Zhang, Org. Biomol. Chem. 2016, 14, 3016–3021; (d) X.
X. Liu, Z. Y. Wu, X. L. Luo, Y. Q. He, X. Q. Zhou, Y. X. Fan, G.
S. Huang, RSC Adv. 2016, 6, 71485–71488; (e) J. Y. Jiao, Y. J.
Mao, A. W. Feng, X. F. Li, M. T. Li, X. H. Zhang, Tetrahedron
2017, 73, 1482–1488; (f) H. Guo, M. Chen, P. Jiang, J. Chen, L.
Pan, M. Wang, C. Xie, Y. Zhang, Tetrahedron 2015, 71, 70-76;
(g) Y. Long, L. Pan, X. Zhou, Molecules 2019, 24, 535-548.
8. X. He, Y. Xu, L. Kong, H. Wu, D. Ji, Z. Wang, Y. Xu, Q. Zhu,
Org. Chem. Front. 2017, 4, 1046–1050.
A test tube was filled with 10 mL of CH2Cl2, in which N-8-
quinolinyl-benzamide (5 mmol, 1.240 g), DBDMH (2.75 mmol,
786.5 mg) were dissolved. The reagent solutions were pumped
into PTFE-FEP tubes (1/32 inner diameter) through pump (Syrris
Ltd) at a flow rate of 53.3 µL · min-1. The solution then
immediately entered a 1.6 mL convection flow coil (CFC) reactor
(1/32 inner diameter) at a flow rate of 53.3 µL·min-1, which
was maintained at ambient temperature (residence time = 30 min).
The flow process was run continuously for 210 min. The product
stream exiting the reactor was collected in a test tube and then
concentrated under vacuum. After evaporation, the residue was
purified by column chromatography on silica gel (200–300 mesh
size) using petroleum ether/EtOAc as the eluent to give 1.39 g of
the product. This flow process gave a product output of 397
mg·h-1.
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Acknowledgement
This work was supported by the National Natural Science
Foundation of China (NSFC) (Project Nos. 21890318 and
21176039).
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