Iron(III)-catalyzed highly regioselective halogenation of 8-amidoquinolines in water

Article abstract of DOI:10.3390/molecules24030535

A simple protocol of iron(III)-catalyzed halogenation of 8-amidoquinolines in water under mild conditions was developed, affording the 5-halogenlated products in good to excellent yields up to 98%. The reaction mechanism most likely involves a single-elec

Full text of DOI:10.3390/molecules24030535

molecules
Article
Iron(III)-Catalyzed Highly Regioselective
Halogenation of 8-Amidoquinolines in Water
Yang Long †, Lei Pan † and Xiangge Zhou *
College of Chemistry, Sichuan University, Chengdu 610064, China; elitelyhere@163.com (Y.L.);
panleiscu@163.com (L.P.)
* Correspondence: zhouxiangge@scu.edu.cn; Tel.: +86-28-85412904
† These authors contributed equally to this work.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Kei Saito
Received: 27 December 2018; Accepted: 31 January 2019; Published: 1 February 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: A simple protocol of iron(III)-catalyzed halogenation of 8-amidoquinolines in water under
mild conditions was developed, affording the 5-halogenlated products in good to excellent yields up
to 98%. The reaction mechanism most likely involves a single-electron transfer (SET) process.
Keywords: 8-amidoquinoline; iron; catalysis; water
1. Introduction
Quinolines are an important kind of structural motif found in numerous bioactive molecules and
natural products with applications in pharmaceutical chemistry. Over the past decades, the quinoline
framework has drawn significant attention due to its frequent occurrence in bioactive natural
products, agrochemicals, and functional materials (Scheme 1) [
achievement of using 8-amidoquinoline as a bidentate directing group by Daugulis [
1
–
8
]. In addition, with the seminal
], a great
9
deal of C-H functionalization reaction has been realized [10]. Therefore, the development of facile
and efficient methods to halogenate quinolines is highly necessary. However, compared with
well-developed functionalization of quinoline’s C2, C3, and C8 positions [11
to the C5-functionalization are still less studied.
–19], the approaches
O
NH2
N
NH
N
N
N
N
N
H
Cl
Cl
Br
Antitumor agents
Nervous system agents
O
NH
N
N
Cl HN
N
N
O
O
N
O
O
Antimalarials
Anti-Alzheimer agents
Scheme 1. Examples of biologically active compounds containing quinoline motifs.
Recently, Stahl and co-workers reported Cu(I) catalyzed C5 chlorination of 8-amidoquinoline
amides by using LiCl as a chlorination reagent [20]. Similarly, Zhang, Li, Huang, etc. described
Molecules 2019, 24, 535; doi:10.3390/molecules24030535
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copper-catalyzed C5 C-H halogenation of 8-amidoquinolines (Scheme 2a) [21
–
27]. Meanwhile,
Li and other groups also reported transition metal-free C5 halogenation of 8-amidoquinolines
(Scheme 2b) [28–31]. Although approaches to the C5 halogenation have been developed to a certain
extent, the work mentioned above still has some drawbacks: (i) usually there was a requirement
of some complex oxidants, such as N-fluorobis(benzenesulfon)imide (NFSI), PhI(OAc)2, oxone, etc.;
(ii) the halogen reagents were expensive, low cost resources like Br2 or I2 that hardly reacted effectively
in these systems [25]; (iii) normally there was usage of an organic solvent, while using water as the sole
solvent was pretty rare [32]; (iv) some reactions needed harsh conditions, such as high temperature or
inert atmosphere. In continuation of our recent work of aqueous catalysis [33–40], herein is reported
iron-catalyzed remote C5 C-H-halogenation of 8-amidoquinolines in water by using NXS and X2
(X = Br, I)) as effective halogen sources (Scheme 2c). Notably, we think this protocol is environmentally
friendly with the following novelties: (i) water as a solvent and air as an oxidant; (ii) cheap iron
salt as the catalyst at mild reaction conditions at room temperature [41]; (iii) easily available and
budget-friendly halogen reagents.
Scheme 2. C5 halogenation of 8-amidoquinoline amides.
(a) Cu-catalyzed halogenation of
8-amidoquinoline amides; ( ) transition metal-free halogenation of 8-amidoquinoline amides;
b
(c) Fe(III)-catalyzed halogenation of 8-amidoquinoline amides.
2. Results and Discussion
Initially, N-(quinolin-8-yl)pivalamide, N-bromo-succinimide (NBS) or Br2 were treated as model
substrates to optimize the reaction conditions. As shown in Table 1, no desired product was observed
under an inert atmosphere (entry 1), indicating the indispensability of the oxidant. Furthermore,
although the product could be obtained with 91% yield by NBS without a catalyst, the yield was
only 35% with Br2 as a halogen source (entry 2). Thus, in order to make both halogen reagents
react well, a variety of metal salts including Pd(II), Cu(II), Co(II), and Fe(III) were then evaluated.
To our delight, metal salts were helpful for the catalysis, especially in the case of Br2 as a halogen
source, the reactivity of which was improved to the same level as NBS (entries 3–7). Considering
the efficiency, low cost, and environmental friendliness, Fe(NO3)3 9H2O was selected as a catalyst
·
for the further studies. The oxidant was another important factor that affected the results. Simple
silver salts such as Ag2O and Ag2CO3 gave similar yields as air (entries 8 and 9), while AgOAc raised
the yield to about 75% (entry 10). Interestingly, the yield increased dramatically to about 90% in the
case of CH3(CH2)5COOAg (entry 11), indicating the positive effect of a long chain carboxylic acid ion,
which might function as a phase transfer reagent [42]. Indeed, when the air was used as an oxidant,
the combination of CH3(CH2)5COOH and NaHCO3 resulted in the best yield of 95% for both halogen

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reagents (entry 12). In summary, the optimal conditions consist of quinolines (0.3 mmol), NBS or Br2
(0.6 mmol), Fe(NO3)3 9H2O (5 mol%), NaHCO3 (0.3 mmol), and CH3(CH2)5COOH (0.3 mmol) at room
temperature for 24 h in the air.
·
a
Table 1. Optimization of the reaction conditions.
Yield [%] b
Entry
Catalyst (%)
Additive
Using Br2
Using NBS
1 c
2
3
4
5
6
7
8
9
-
-
-
-
-
-
-
-
-
0
0
35
47
43
39
68
63
59
64
73
89
91
67
65
58
68
65
65
69
75
90
Pd(OAc)2 (10)
Cu(OAc)2 (20)
Co(OAc)2·9H2O (20)
Fe(NO3)3·9H2O (5)
FeCl3·9H2O (5)
Fe(NO3)3·9H2O (5)
Fe(NO3)3·9H2O (5)
Fe(NO3)3·9H2O (5)
Fe(NO3)3·9H2O (5)
Ag2O
Ag2CO3
AgOAc
CH3(CH2)5COOAg
CH3(CH2)5COOH,
10
11
12
Fe(NO3)3·9H2O (5)
95
95
d
NaHCO3
a
Unless otherwise noted, the reactions were carried out with N-(quinolin-8-yl)pivalamide (0.3 mmol),
N-bromo-succinimide (NBS) or Br2 (0.6 mmol), a catalyst (5–20%), an additive (0.6 mmol) in water (1 mL) under
b
c
d
air atmosphere at room temperature for 24 h. Isolated yields. N2 atmosphere. CH3(CH2)5COOH (0.3 mmol),
NaHCO3 (0.3 mmol).
With the optimized conditions in hand, we subsequently examined the scope of quinoline
derivatives, as shown in Scheme 3. Overall, different substrates provided moderate to excellent
yields, and both halogen reagents could efficiently realize the reaction, while much lower reactive
activity was found in the previous reports [26]. The length of the linear alkyl chain showed few effects
on the reaction, affording similar results around 90% yields (Scheme 3a–d). Various branched chain
alkyl groups also gave excellent yield (Scheme 3e–j). Meanwhile, different aryl groups were also
compatible in this system. The substrates bearing para-methyl chloro groups gave excellent yields up
to 95% (Scheme 3l,m), para-trifluoromethyl groups gave a moderate yield of about 73% (Scheme 3n),
and the meta-chloro and methoxyl group gave a good yield (Scheme 3o,p). Replacement of the aryl
with the ethylphenyl and thienyl groups were also well-tolerated (Scheme 3q,r). The methyl group on
the C2 position of the quinoline ring were also compatible (Scheme 3s). Moreover, the structure of the
product (Scheme 3l) was confirmed by X-ray crystallography (Figure 1) [CCDC 1480727, for detailed
crystal data, see Supplementary Information (SI)].

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Scheme 3. Iron-catalyzed C-H bromination. Reaction conditions A: 1 (0.3 mmol), NBS (0.6 mmol),
CH3(CH2)5COOH (0.3 mmol), NaHCO3 (0.3 mmol), and Fe(NO3)3 9H2O (5 mol%) in water (1 mL) at rt
·
for 24 h. Reaction conditions B: 1 (0.3 mmol), Br2 (0.6 mmol), CH3(CH2)5COOH (0.3 mmol), NaHCO3
(0.3 mmol), and Fe(NO3)3·9H2O (5 mol%) in water (1 mL) at rt for 24 h.
Figure 1. Single-crystal X-ray structure of 2l.
In an endeavor to expand the scope of this methodology, NIS and I2 were treated as halogen
reagents. As shown in Scheme 4, iodination reaction could also be fulfilled (although with low yields
around 40%) by using I2 or NIS (3c, 3f). The lower yield of iodination than that of bromination
might have been due to the lower reactivity of the iodine free radical and the instability of iodo
products [43,44].

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Scheme 4. Iron-catalyzed C-H halogenation. Reaction conditions C: 1 (0.3 mmol), NIS (0.6 mmol),
CH3(CH2)5COOH (0.3 mmol), NaHCO3 (0.3 mmol), and Fe(NO3)3 9H2O (5 mol%) in water (1 mL) at
·
rt for 24 h. Reaction conditions D: 1 (0.3 mmol), I2 (0.6 mmol), CH3(CH2)5COOH (0.3 mmol), NaHCO3
(0.3 mmol), and Fe(NO3)3·9H2O (5 mol%) in water (1 mL) at rt for 24 h.
Furthermore, the scaled-up reaction was carried out, giving quantities of the 2c in 90% (Scheme 5),
which indicated it as a facile route to the desired product on a more synthetically useful scale.
Scheme 5. Gram-scale iron-catalyzed C-H bromination of 1c.
In order to expand the application of this protocol, N-(5-bromoquinolin-8-yl)pivalamide was
reacted with boronic acid to give a series of derivatives by simple Suzuki coupling reactions in
moderate to good yields ranging from 54% to 84%(Scheme 6) [45,46].
Scheme 6. Suzuki coupling reaction.

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Next, radical trapping experiments were carried out, as shown in Scheme 7, and the addition
of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) drastically hampered the reaction. In addition,
an EPR experiment was done (for detailed EPR spectra, see SI). Both results suggested that the radical
mechanism might be involved in the reaction.
Scheme 7. Radical trapping experiments.
At last, three analogous substrates were also investigated. As shown in Scheme 8,
8-aminoquinoline and quinoline gave 40% and none of the product, respectively, which suggested
the necessity of the protected amino group during the reaction (Scheme 8a). Moreover,
N-(1-naphthyl)carboxamide generated a mixture of brominated byproducts, indicating that a chelation
of iron with N,N-bidentate 8-aminoquinoline might play a predominant role in the reaction (Scheme 8c).
Scheme 8. The exploration of the analogous substrates.
Based on our work, as well as existing literatures [20
proposed, as shown in Scheme 9. At first, substrate 1 and Fe(III) species formed complex A, which
was transformed to be complex B after deprotonation [41 47]. Then, B, which may have influenced the
electron density of the quinoline ring at the C5-H position [47 48], was attacked by a bromine radical
–27], a plausible reaction pathway was
,
,
from the halogen reagent to form complex C by a single electron transfer process (SET). The complex C
soon transformed into D through oxidation. After generation of the intermediate E through the proton
transfer process (PT), a metal dissociation process gained the terminal product 2 and Fe(III) species,
and the catalytic cycle was completed. Furthermore, considering that the reaction could be carried

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out without a catalyst, although the yield was low, a metal-free halogenation mechanism reported by
Xu [32] also may have been involved in the reaction.
Scheme 9. Plausible mechanism for C5 halogenation of quinolines.
3. Materials and Methods
3.1. General Experimental Procedures
Unless otherwise noted, all the reactions were performed under air atmosphere. All reagents
were used without purification as commercially available. All reactions were monitored by thin layer
chromatography. Analytical thin layer chromatography (TLC) was performed using silica gel GF254
plates. Chemical yields refer to pure isolated substances. Column chromatography was performed
using silica gel (200–300 mesh or 300–400 mesh) eluting with petroleum ether and ethyl acetate.
1
All products were characterized by their NMR spectra. H-NMR spectra were recorded at 400 MHz
and 13C-NMR spectra at 100 MHz (Bruker DPX, Bruker, Madison, WI, USA) with CDCl3 as a solvent.
Chemical shifts were reported in ppm using TMS as the internal standard.
3.2. Synthesis of Starting Materials
To a 50 mL single neck flask charged with CH2Cl2 (20 mL) was added 8-aminoquinoline (10 mmol)
and triethylamine (11 mmol) and stirred at room temperature for 5 min, then the reaction solution
was cooled in an ice bath. The acid chloride (12 mmol) was added dropwise (if solid, it was dissolved
with CH2Cl2). The reaction solution was stirred overnight. When it was completed monitored by TLC,
the mixture was filtered through a pad of Celite, the solid was washed with ethyl acetate (30 mL),
and the organic layer was washed with 1 M NaHCO3 of aqueous solution (3
organic layer was dried with Na2SO4, filtered, and the solvent was removed under reduced pressure.
The product was finally obtained by column chromatography on silica gel (PE/EtOAc = 20/1).
×
15 mL), then the
3.3. General Procedures for Iron-Catalyzed Halogenation C5-H of 8-Amidoquinolines under Mild Conditions
in Water
Reaction conditions A: A mixture of 1 (0.3 mmol), NBS (0.6 mmol), Fe(NO3)3 9H2O(5 mol%),
·
CH3(CH2)5COOH (0.3 mmol), NaHCO3 (0.3 mmol) in water (1.0 mL) in a 20 mL Schlenk
tube was stirred at room temperature for 24 h. Then, the mixture was extracted with EtOAc

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(10 mL × 4). The combined organic layer was dried with Na2SO4 and filtered through a pad of
Celite. The solvent was removed under reduced pressure and the residue was purified by silica gel
column chromatography using PE/EtOAc (20/1) as an eluent to afford the products.
Reaction conditions B: A mixture of 1 (0.3 mmol), Br2 (0.6 mmol), Fe(NO3)3 9H2O (5 mol%),
·
CH3(CH2)5COOH (0.3 mmol), NaHCO3 (0.3 mmol) in water (1.0 mL) in a 20 mL Schlenk
tube was stirred at room temperature for 24 h. Then, the mixture was extracted with EtOAc
(10 mL × 4). The combined organic layer was dried with Na2SO4 and filtered through a pad of
Celite. The solvent was removed under reduced pressure and the residue was purified by silica
gel column chromatography using PE/EtOAc (20/1) as an eluent to afford the corresponding
halogenation products.
Reaction conditions C: A mixture of 1 (0.3 mmol), NIS (0.6 mmol), Fe(NO3)3 9H2O(5 mol%),
·
CH3(CH2)5COOH (0.3 mmol), NaHCO3 (0.3 mmol) in water (1.0 mL) in a 20 mL Schlenk
tube was stirred at room temperature for 24 h. Then, the mixture was extracted with EtOAc
(10 mL × 4). The combined organic layer was dried with Na2SO4 and filtered through a pad of
Celite. The solvent was removed under reduced pressure and the residue was purified by silica gel
column chromatography using PE/EtOAc (20/1) as an eluent to afford the products.
Reaction conditions D: A mixture of 1 (0.3 mmol), I2 (0.6 mmol), Fe(NO3)3 9H2O(5 mol%),
·
CH3(CH2)5COOH (0.3 mmol), NaHCO3 (0.3 mmol) in water (1.0 mL) in a 20 mL Schlenk
tube was stirred at room temperature for 24 h. Then, the mixture was extracted with EtOAc
(10 mL × 4). The combined organic layer was dried with Na2SO4 and filtered through a pad of
Celite. The solvent was removed under reduced pressure and the residue was purified by silica gel
column chromatography using PE/EtOAc (20/1) as an eluent to afford the products.
N-(5-Bromoquinolin-8-yl)acetamide (2a), 1H-NMR (400 MHz, CDCl3)
1.5 Hz, 1H), 8.61 (d, J = 8.4 Hz, 1H), 8.46 (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 (100 MHz, CDCl3)
= 168.78, 148.55, 138.81, 135.90, 134.37, 130.85,
127.05, 122.62, 116.82, 114.10, 25.18. HRMS: calculated [C11H10BrN2O]+: 264.9971, found: 264.9964 [26].
δ = 9.72 (s, 1H), 8.77 (dd, J = 4.2,
δ
N-(5-Bromoquinolin-8-yl)propionamide (2b), 1H-NMR (400 MHz, CDCl3)
δ = 9.76 (s, 1H), 8.78 (dd, J = 4.2,
1.6 Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.47 (dd, J = 8.5, 1.6 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 8.5,
4.2 Hz, 1H), 2.59 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ = 172.49,
148.55, 138.94, 135.91, 134.43, 130.90, 127.09, 122.61, 116.82, 113.95, 31.25, 9.68. HRMS: calculated
[C12H12BrN2O]+: 279.0128, found: 279.0122 [31].
N-(5-Bromoquinolin-8-yl)butyramide (2c), 1H-NMR (400 MHz, CDCl3)
δ = 9.75 (s, 1H), 8.78 (dd, J = 4.2,
1.5 Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.47 (dd, J = 8.5, 1.5 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.52 (dd,
J = 8.5, 4.2 Hz, 1H), 2.56–2.50 (m, 2H), 1.90–1.78 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H). 13C-NMR (100 MHz,
CDCl3) δ = 171.75, 148.50, 138.87, 135.92, 134.38, 130.88, 127.06, 122.58, 116.84, 113.94, 40.11, 19.05, 13.83.
HRMS: calculated [C13H14BrN2O]+: 293.0284, found: 293.0284 [26].
N-(5-Bromoquinolin-8-yl)hexanamide (2d), 1H-NMR (400 MHz, CDCl3)
δ = 9.74 (s, 1H), 8.77 (dd, J = 4.2,
1.6 Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.46 (dd, J = 8.5, 1.6 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.51 (dd,
J = 8.5, 4.2 Hz, 1H), 2.62–2.44 (m, 2H), 1.90–1.74 (m, 2H), 1.45–1.32 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H).
13C-NMR (100 MHz, CDCl3)
δ = 171.89, 148.52, 138.89, 135.83, 134.42, 130.85, 127.03, 122.57, 116.79,
113.92, 38.19, 31.45, 25.27, 22.48, 13.99. HRMS: calculated [C15H18BrN2O]+: 321.0597, found: 321.0587.
1
N-(5-Bromoquinolin-8-yl)isobutyramide (2e), H-NMR (400 MHz, CDCl3)
δ = 9.86 (s, 1H), 8.80 (d,
J = 4.2 Hz, 1H), 8.67 (d, J = 8.4 Hz, 1H), 8.48 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.53 (dd,
J = 8.5, 4.2 Hz, 1H), 2.76 (dt, J = 13.8, 6.9 Hz, 1H), 1.35 (d, J = 6.9 Hz, 6H). 13C-NMR (100 MHz, CDCl3)
δ
= 175.73, 148.56, 139.07, 135.92, 134.49, 130.89, 127.09, 122.58, 116.86, 113.93, 37.12, 19.66. HRMS:
calculated [C13H14BrN2O]+: 293.0284, found: 293.0284 [28].

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N-(5-Bromoquinolin-8-yl)pivalamide (2f), 1H-NMR (400 MHz, CDCl3) δ = 10.13 (s, 1H), 8.71 (dd, J = 4.2,
1.6 Hz, 1H),8.59 (d, J = 8.4 Hz, 1H), 8.37 (dd, J = 8.5, 1.6 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.43 (dd,
J = 8.5, 4.2 Hz, 1H), 1.33 (s, 9H). 13C-NMR (100 MHz, CDCl3)
δ = 176.19, 147.60, 138.34, 134.79, 133.53,
129.83, 126.02, 121.50, 115.62, 112.82, 39.32, 26.64. HRMS: calculated [C14H15BrN2NaO]+: 329.0260,
found: 329.0253 [26].
N-(5-Bromoquinolin-8-yl)-2,2-dimethylbutanamide (2g), 1H-NMR (400 MHz, CDCl3)
δ = 10.10 (s, 1H), 8.71
(d, J = 4.2 Hz, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.44–8.30 (m, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.43 (ddd, J = 8.5,
4.2, 0.7 Hz, 1H), 1.66 (q, J = 7.5 Hz, 2H), 1.29 (s, 6H), 0.85 (t, J = 7.5 Hz, 3H). 13C-NMR (100 MHz, CDCl3)
δ
= 175.62, 147.62, 138.35, 134.80, 133.51, 129.85, 126.04, 121.50, 115.61, 112.78, 43.05, 33.04, 23.99, 8.26.
HRMS: calculated [C15H18BrN2O]+: 321.0597, found: 321.0587.
N-(5-Bromoquinolin-8-yl)-3-chloro-2,2-dimethylpropanamide (2h), 1H-NMR (400 MHz, CDCl3)
δ = 10.21 (s,
1H), 8.71 (dd, J = 4.2, 1.6 Hz, 1H), 8.58 (d, J = 8.4 Hz, 1H), 8.36 (dd, J = 8.5, 1.6 Hz, 1H), 7.67 (d, J = 8.4 Hz,
1H), 7.43 (dd, J = 8.5, 4.2 Hz, 1H), 3.69 (s, 2H), 1.45 (s, 6H). 13C-NMR (100 MHz, CDCl3) δ = 172.42,
147.77, 138.28, 134.81, 132.99, 129.74, 126.02, 121.62, 115.89, 113.44, 51.65, 44.79, 22.61. HRMS: calculated
[C14H14BrClN2NaO]+: 362.9870, found: 362.9869.
1
N-(5-Bromoquinolin-8-yl)-3-cyclopentylpropanamide (2i), H-NMR (400 MHz, CDCl3)
δ = 9.76 (s, 1H),
8.84–8.76 (m, 1H), 8.66 (d, J = 8.4 Hz, 1H), 8.48 (dt, J = 8.5, 1.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.53
(ddd, J = 8.5, 4.2, 0.9 Hz, 1H), 2.61–2.53 (m, 2H), 1.88–1.78 (m, 5H), 1.69–1.47 (m, 4H), 1.17 (tt, J = 14.0,
6.8 Hz, 2H). 13C-NMR (100 MHz, CDCl3)
δ = 172.02, 148.55, 138.93, 135.90, 134.46, 130.90, 127.08,
122.59, 116.84, 113.94, 39.74, 37.55, 32.55, 31.77, 25.20. HRMS: calculated [C17H19BrN2NaO]+: 369.0573,
found: 369.0566.
N-(5-Bromoquinolin-8-yl)-4-methylpentanamide (2j), 1H-NMR (400 MHz, CDCl3)
δ = 9.66 (s, 1H), 8.69
(dd, J = 4.2, 1.4 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.37 (dd, J = 8.5, 1.5 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H),
7.42 (dd, J =8.5, 4.2 Hz, 1H), 2.54–2.40 (m, 2H), 1.68–1.55 (m, 3H), 0.88 (d, J = 6.4 Hz, 6H). 13C-NMR
(100 MHz, CDCl3)
δ = 172.06, 148.54, 138.91, 135.91, 134.44, 130.90, 127.07, 122.59, 116.85, 113.94, 36.24,
34.34, 27.83, 22.41. HRMS: calculated [C15H18BrN2O]+: 321.0597, found: 321.0588 [32].
N-(5-Bromoquinolin-8-yl)benzamide (2k), 1H-NMR (400 MHz, CDCl3)
= 10.65 (s, 1H), 8.87–8.74 (m, 2H),
8.47 (dd, J = 8.5, 1.5 Hz, 1H), 8.10–8.00 (m, 2H), 7.79 (d, J = 8.4 Hz, 1H), 7.61–7.49 (m, 4H). 13C-NMR
(100 MHz, CDCl3) = 165.48, 148.78, 139.42, 136.16, 134.86, 134.51, 132.07, 131.05, 128.88, 127.33, 122.79,
117.13, 114.48. HRMS: calculated [C16H12BrN2O]+: 327.0128, found: 327.0120 [26].
N-(5-Bromoquinolin-8-yl)-4-methylbenzamide (2l), 1H-NMR (400 MHz, CDCl3) = 10.62 (s, 1H), 8.89–8.72
(m, 2H), 8.46 (dd, J = 8.5, 1.5 Hz, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 8.5,
4.2 Hz, 1H), 7.31 (d, J = 7.9 Hz, 2H), 2.43 (s, 3H). 13C-NMR (100 MHz, CDCl3)
= 165.48, 148.71,
δ
δ
δ
δ
142.62, 139.41, 136.17, 134.62, 132.04, 131.08, 129.54, 127.34, 127.30, 122.74, 117.10, 114.29, 21.61. HRMS:
calculated [C17H14BrN2O]+: 341.0284, found: 341.0284 [24].
N-(5-Bromoquinolin-8-yl)-4-chlorobenzamide (2m), 1H-NMR (400 MHz, CDCl3)
δ = 10.63 (s, 1H), 8.84 (dd,
J = 4.2, 1.6 Hz, 1H), 8.76 (d, J = 8.4 Hz, 1H), 8.51 (dd, J = 8.5, 1.6 Hz, 1H), 7.98 (d, J = 8.6 Hz, 2H), 7.81 (d,
J = 8.4 Hz, 1H), 7.57 (dd, J = 8.5, 4.2 Hz, 1H), 7.52–7.49 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ = 164.33,
148.82, 139.31, 138.35, 136.21, 134.22, 133.20, 131.00, 129.13, 128.73, 127.30, 122.83, 117.18, 114.72. HRMS:
calculated [C16H11BrClN2O]+: 360.9738, found: 360.9725 [32].
N-(5-Bromoquinolin-8-yl)-4-(trifluoromethyl)benzamide (2n), 1H-NMR (400 MHz, CDCl3)
8.83 (dd, J = 4.2, 1.5 Hz, 1H), 8.76 (d, J = 8.4 Hz, 1H), 8.51 (dd, J = 8.5, 1.5 Hz, 1H), 8.14 (d, J = 8.2 Hz,
2H), 7.80 (dd, J = 8.4, 3.4 Hz, 3H), 7.57 (dd, J = 8.5, 4.2 Hz, 1H).. 13C-NMR (100 MHz, CDCl3)
= 163.92,
δ = 10.70 (s, 1H),
δ
148.91, 139.23, 138.00, 136.14, 133.98, 133.78, 130.91, 127.75, 127.24, 125.91 (q, J = 3.7 Hz), 122.89, 122.33,
117.20, 115.02. HRMS: calculated [C17H10BrF3N2NaO]+: 416.9821, found: 416.9817 [31].

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1
N-(5-Bromoquinolin-8-yl)-3-chlorobenzamide (2o), H-NMR (400 MHz, CDCl3)
δ
= 10.66 (s, 1H), 8.88
(dd, J = 4.2, 1.6 Hz, 1H), 8.79 (d, J = 8.4 Hz, 1H), 8.55 (dd, J = 8.5, 1.6 Hz, 1H), 8.04 (t, J = 1.8 Hz, 1H),
7.96–7.89 (m, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.66–7.53 (m, 2H), 7.49 (t, J = 7.8 Hz, 1H). 13C-NMR (100 MHz,
CDCl3) δ = 162.94, 147.88, 138.32, 135.58, 135.08, 134.06, 133.12, 131.03, 129.91, 129.11, 126.66, 126.24,
124.23, 121.82, 116.14, 113.80. HRMS: calculated [C16H10BrClN2O]+: 360.9743, found: 360.9726 [24].
1
N-(5-Bromoquinolin-8-yl)-3-methoxylbenzamide (2p), H-NMR (400 MHz, CDCl3)
δ = 10.70 (s, 1H),
9.01–8.73 (m, 2H), 8.55 (dd, J = 8.5, 1.6 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.66–7.57 (m, 3H), 7.46 (t,
J = 8.2 Hz, 1H), 7.13 (ddd, J = 8.3, 2.5, 1.0 Hz, 1H), 3.92 (s, 3H). 13C-NMR (100 MHz, CDCl3)
δ
= 165.30,
160.04, 148.84, 139.45, 136.35, 136.06, 134.50, 131.00, 129.86, 127.28, 122.79, 119.06, 118.19, 117.04, 114.50,
112.71, 55.55. HRMS: calculated [C17H14BrN2O2]+: 357.0239, found: 357.0217 [24].
N-(5-Bromoquinolin-8-yl)-3-phenylpropanamide (2q), 1H-NMR (400 MHz, CDCl3)
δ = 9.72 (s, 1H), 8.74
(dd, J = 4.2, 1.6 Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.46 (dd, J = 8.5, 1.6 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H),
7.50 (dd, J = 8.5, 4.2 Hz, 1H), 7.31–7.27 (m, 4H), 7.24–7.17 (m, 1H), 3.17–3.10 (m, 2H), 2.87 (dd, J = 8.7,
7.0 Hz, 2H). 13C-NMR (100 MHz, CDCl3)
δ = 170.77, 148.55, 140.66, 138.88, 135.88, 134.30, 130.88,
128.62, 128.44, 127.07, 126.34, 122.64, 116.92, 114.13, 39.71, 31.40. HRMS: calculated [C18H15BrN2NaO]+:
377.0260, found: 377.0256 [22].
1
N-(5-Bromoquinolin-8-yl)thiophene-2-carboxamide (2r), H-NMR (400 MHz, CDCl3)
δ = 10.58 (s, 1H),
8.89 (dd, J = 4.2, 1.5 Hz, 1H), 8.75 (d, J = 8.4 Hz, 1H), 8.58 (dd, J = 8.5, 1.5 Hz, 1H), 7.86 (dd, J = 4.8,
3.7 Hz, 2H), 7.65–7.53 (m, 2H), 7.20 (dd, J = 4.9, 3.8 Hz, 1H). 13C-NMR (100 MHz, CDCl3)
δ
= 159.95,
148.77, 139.73, 139.11, 136.04, 134.20, 131.19, 130.97, 128.60, 127.92, 127.23, 122.76, 117.00, 114.44. HRMS:
calculated [C14H10BrN2OS]+: 332.9692, found: 332.9691 [24].
N-(5-Bromo-2-methyl-8-quinolinyl)- pivalamide (2s), 1H-NMR (400 MHz, CDCl3)
J = 8.4 Hz, 1H), 8.35 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 2.76 (s, 3H), 1.42
(s, 6H). 13C-NMR (100 MHz, CDCl3)
= 177.15, 157.71, 138.78, 135.93, 133.89, 129.85, 125.31, 123.34,
116.62, 113.85, 40.39, 27.64, 25.17. HRMS: calculated [C15H18BrN2O]+: 321.0603, found: 321.0601 [30].
δ = 10.31 (s, 1H), 8.63 (d,
δ
N-(5-Iodoquinolin-8-yl)butyramide (3c), 1H-NMR (400 MHz, CDCl3)
= 9.79 (s, 1H), 8.77 (dd, J = 4.2,
δ
1.5 Hz, 1H), 8.57 (d, J = 8.3 Hz, 1H), 8.37 (dd, J = 8.5, 1.5 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.53 (dd,
J = 8.5, 4.2 Hz, 1H), 2.56–2.52 (m, 2H), 1.85 (dd, J = 14.9, 7.4 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H). 13C-NMR
(100 MHz, CDCl3)
δ = 171.79, 148.65, 140.67, 138.88, 138.25, 135.42, 129.51, 123.10, 117.76, 89.06, 40.17,
19.06, 13.84. HRMS: calculated [C13H14IN2O]+: 341.0145, found: 341.0139 [26].
N-(5-Iodoquinolin-8-yl)pivalamide (3f), 1H-NMR (400 MHz, CDCl3)
= 10.26 (s, 1H), 8.76 (dd, J = 4.2,
1.5 Hz, 1H), 8.56 (d, J = 8.3 Hz, 1H), 8.33 (dd, J = 8.5, 1.6 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.51 (dd,
δ
J = 8.5, 4.2 Hz, 1H), 1.42 (s, 9H). 13C-NMR (100 MHz, CDCl3)
δ = 176.27, 147.72, 139.59, 138.26, 137.19,
134.49, 128.43, 122.03, 116.52, 87.94, 39.36, 26.63. HRMS: calculated [C14H16IN2O]+: 355.0302, found:
355.0292 [31].
3.4. General Procedures for Suzuki Coupling Reaction of N-(5-Bromoquinolin-8-yl)pivalamide (4a as
an Example)
A mixture of 2f (0.3 mmol), phenylboronic acid (0.36 mmol), PdCl2 (5 mol%), KOH (0.6 mmol),
in solvent (2-propanol/water = 1/1.5, 1.0 mL) in a 20 mL Schlenk tube was stirred at 80 ◦C for 24 h.
Then, the mixture was extracted with EtOAc (10 mL
×
4). The combined organic layer was dried with
Na2SO4 and filtered through a pad of Celite. The solvent was removed under reduced pressure and
the residue was purified by silica gel column chromatography using PE/EtOAc (20/1) as an eluent to
afford the products.
N-(5-Phenylquinolin-8-yl)pivalamide (4a), 1H-NMR (400 MHz, CDCl3)
8.29 (dd, J = 8.5, 1.6 Hz, 1H), 7.54–7.39 (m, 7H), 1.46 (s, 9H). 13C-NMR (101 MHz, CDCl3) δ = 177.34,
δ = 10.38 (s, 1H), 9.00–8.71 (m, 2H),

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148.04, 139.27, 138.81, 134.76, 134.11, 134.03, 130.14, 128.52, 128.02, 127.45, 126.27, 121.51, 115.81, 40.42,
27.80. HRMS: calculated [C20H21N2O]+: 305.1648, found: 305.1626 [30].
N-(5-(4-Methoxyphenyl)quinolin-8-yl)pivalamide (4b), 1H-NMR (400 MHz, CDCl3)
δ = 10.35 (s, 1H), 8.83
(dd, J = 4.8, 3.2 Hz, 2H), 8.30 (dd, J = 8.5, 1.6 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.5,
4.2 Hz, 1H), 7.39–7.35 (m, 2H), 7.05–7.00 (m, 2H), 3.89 (s, 3H), 1.45 (s, 9H). 13C-NMR (101 MHz, CDCl3)
δ = 177.28, 159.12, 147.90, 138.83, 134.93, 133.80, 133.77, 131.65, 131.18, 127.90, 126.51, 121.34, 116.03,
113.96, 55.41, 40.39, 27.80. HRMS: calculated [C21H23N2O2]+: 355.1754, found: 355.1736 [30].
N-(5-(Pent-1-en-1-yl)quinolin-8-yl)pivalamide (4c), 1H-NMR (400 MHz, CDCl3)
δ = 10.30 (s, 1H), 8.80
(dd, J = 4.2, 1.6 Hz, 1H), 8.75 (d, J = 8.1 Hz, 1H), 8.47 (dd, J = 8.6, 1.6 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H),
7.46 (dd, J = 8.5, 4.2 Hz, 1H), 6.96 (d, J = 15.6 Hz, 1H), 6.23 (dt, J = 15.5, 7.0 Hz, 1H), 2.29 (m, J = 7.2,
1.5 Hz, 2H), 1.62–1.51 (m, 2H), 1.43 (d, J = 1.6 Hz, 9H), 1.00 (t, J = 7.4 Hz, 3H). 13C-NMR (100 MHz,
CDCl3) δ = 177.14, 147.84, 138.72, 134.26, 133.70, 132.79, 129.66, 125.77, 125.26, 124.41, 121.12, 116.21,
40.35, 35.54, 27.77, 22.57, 13.81. HRMS: calculated [C19H25N2O]+: 297.1961, found: 297.1950 [30].
N-(5-(4-Chlorophenyl)quinolin-8-yl)pivalamide (4d), 1H-NMR (400 MHz, CDCl3)
8.96–8.71 (m, 2H), 8.23 (dd, J = 8.5, 1.6 Hz, 1H), 7.50–7.35 (m, 6H), 1.45 (s, 9H). 13C-NMR (101 MHz,
CDCl3) = 177.37, 148.08, 138.76, 137.69, 134.46, 134.42, 133.58, 132.64, 131.38, 128.72, 128.10, 126.16,
121.63, 115.89, 40.42, 27.77. HRMS: calculated [C20H19ClN2NaO]+: 361.1078, found: 361.1069 [30].
δ = 10.36 (s, 1H),
δ
N-(5-(4-Cyanophenyl)quinolin-8-yl)pivalamide (4e), 1H-NMR (400 MHz, CDCl3)
= 10.38 (s, 1H), 8.90–8.82
(m, 2H), 8.19 (dd, J = 8.6, 1.5 Hz, 1H), 7.83–7.74 (m, 2H), 7.61–7.55 (m, 2H), 7.53–7.43 (m, 2H), 1.45
δ
(s, 9H). 13C-NMR (101 MHz, CDCl3)
δ = 177.45, 148.36, 144.13, 138.76, 135.18, 133.90, 132.34, 131.71,
130.82, 128.44, 125.72, 121.98, 118.79, 115.70, 111.28, 40.45, 27.74. HRMS: calculated [C21H19N3NaO]+:
352.1420, found: 352.1411 [30].
4. Conclusions
In summary, we developed an efficient, economical, and environmentally friendly method for
iron(III)-catalyzed C5-H halogenation of quinolines at room temperature in water. Both NXS and X2
could effectively function as halogen agents. The air could act as the oxidant. This transformation
showed a broad substrate scope, good yield, and well-tolerated functionalization. Mechanism studies
suggested that a single electron transfer (SET) mechanism might be involved in the reaction.
Supplementary Materials: The supplementary materials are available online.
Author Contributions: Y.L. and L.P. contributed equally. Y.L., L.P. and X.Z. conceived and designed the
experiments; Y.L. and L.P. performed the experiments and analyzed the data. Y.L., L.P. and X.Z. wrote, read and
approved the paper.
Funding: We are grateful to the National Natural Science Foundation of China (grant No. 21472128) and Sichuan
Science and Technology Program (No. 2018JY560) for financial support.
Acknowledgments: We acknowledge Comprehensive Training Platform of Specialized Laboratory, College of
Chemistry, Sichuan University for HRMS analysis.
Conflicts of Interest: The author declares no conflict of interest.
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Sample Availability: Samples of the compounds 1–4 are available from the authors.
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