Synthesis of Multibromo-Substituted Quinolines by NBS-Mediated Cascade Electrophilic Bromination/Cyclization of N -(3-Phenylprop-2-ynyl)anilines

DOI: 10.1055/a-1396-8198

Source and publish data:

Synthesis p. 2469 - 2476 (2021)

Update date:2022-08-11

Topics:

Authors:

Deng, Si

Ouyang, Wenliang

Bai, Jiang

Song, Xian-Rong

Yang, Ruchun

Xiao, Qiang

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Article abstract of DOI:10.1055/a-1396-8198

A new and convenient protocol is presented here for the synthesis of 3,6,8-tribromoquinolines via cascade cyclization of N -(3-phenylprop-2-ynyl)anilines employing N -bromosuccinimide as an electrophile. The metal-free process is carried out under mild conditions and is compatible with a variety of substituents. The Sonogashira coupling reaction regioselectively occurs at position C-6 of the obtained products.

Full text of DOI:10.1055/a-1396-8198

SYNTHESIS

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart

2021, 53, A–H

paper

S. Deng et al.

Paper

Synthesis

Synthesis of Multibromo-Substituted Quinolines by NBS-Mediated

Cascade Electrophilic Bromination/Cyclization of N-(3-Phenylprop-

2-ynyl)anilines

Si Deng

Wenliang Ouyang

Jiang Bai

(R) Br

(R) H

· Multibromination

· Mild conditions

· Short reaction time

· Gram-scale

· Regioselective cross-coupling

NBS (5.0 equiv)

DCM, air, 10 min

41–95%

Xian-Rong Song

Ruchun Yang*

Qiang Xiao*

21 examples

Institute of Organic Chemistry, Jiangxi Science & Technology

Normal University, Jiangxi Province, Nanchang 330013,

P. R. of China

xiaoqiang@tsinghua.org.cn

ouyangruchun@163.com

Corresponding Authors

Received: 12.01.2021

Accepted after revision: 22.02.2021

Published online: 22.02.2021

1-azido-2-alkynylbenzenes with various halogen electro-

philes (Scheme 1a).^10dThis reaction provided a useful

method for the synthesis of multisubstituted quinolines in

good to high yields. Subsequently, Likhar’s group reported

the synthesis of 2-perfluoroalkyl-3-iodoquinolines employ-

ing an I₂/NaHCO₃system, in which a diverse range of quino-

lines were generated from substrates bearing various per-

fluoroalkyl groups (Scheme 1b).^10eMeanwhile, Pan’s group

reported a novel diiodination of N-(1,3-diarylprop-2-yn-1-

yl)anilines in the presence of NIS, giving the diiodinated

quinolines in moderate to excellent yields. In this reaction,

the electrophilic substitution reaction occurs first, and then

radical cyclization to form the desired products (Scheme

1c).^10fAnother elegant work was developed by Larock’s

group using more readily prepared arylpropargylanilines as

the substrate. A wide variety of monoiodo-substituted

quinolines have been readily synthesized through 6-endo-

dig electrophilic cyclization of arylpropargylanilines in the

presence of an electrophile (ICl, I₂or NIS) and 2 equivalents

of NaHCO₃as base. New 3,6-dibromoquinoline derivatives

could be obtained when bromine was used as electrophilic

reagent. However, no cyclization product was obtained us-

ing NBS (2.0 equiv) as electrophile for this reaction, and

only 4-bromo-N-(3-phenylprop-2-yn-1-yl)aniline was ob-

tained (Scheme 1d).^11a

Quinoline compounds multisubstituted with halogen

atoms, especially bromine atoms, can provide multiple sites

for further coupling reactions. If regioselective coupling is

possible, it will be easy to establish a library of quinoline

compounds. NBS, as an environmentally friendly bromine

source and a metal-free system, proved to be a vital strate-

gy in a series of transformations.¹³Encouraged by Larock’s

work, we envisioned that multibromo-substituted quino-

lines might be obtained through cascade electrophilic bro-

mination and cyclization when excess NBS was applied be-

cause the ortho- and para-positions of aromatic amines

DOI: 10.1055/a-1396-8198; Art ID: ss-2020-n0628-op

Abstract A new and convenient protocol is presented here for the

synthesis of 3,6,8-tribromoquinolines via cascade cyclization of N-(3-

phenylprop-2-ynyl)anilines employing N-bromosuccinimide as an elec-

trophile. The metal-free process is carried out under mild conditions

and is compatible with a variety of substituents. The Sonogashira cou-

pling reaction regioselectively occurs at position C-6 of the obtained

products.

Key words tribromoquinolines, electrophilic cyclization, N-bromosuc-

cinimide, propargylanilines

Quinolines represent the privileged skeletons of a large

number of naturally occurring and pharmacologically ac-

tive compounds which display a broad spectrum of biologi-

cal activities.^1–3A series of methodologies have been devel-

oped for their synthesis.^4–8The most prevalent strategies

for constructing quinoline rings are the classic annulation

reactions, including the Skraup–Doebner–Von Miller syn-

thesis,^8a,bCombes synthesis,^8c,dPfitzinger reaction,^8eCamps

synthesis^8fand Friedländer synthesis,^8gamong others. Al-

though the synthesis of quinolines has been fully devel-

oped, the great need for further development, such as mild-

er reaction conditions, broad functional group compatibili-

ty and higher yield, is still of great urgency.

In recent years, the intramolecular cyclization of

alkynes has proven to be an efficient method for the con-

struction of heterocycles. Our works⁹and that of others^10–12

on the electrophilic cyclization of functionally substituted

alkynes showed that it is a powerful strategy to construct

heterocycles. The alkyne bond is easily activated by electro-

philes such as I₂, ICl, NIS, Br₂or NBS to undergo halogena-

tion/cyclization sequences. As shown in Scheme 1, 3-halo-

quinolines can be obtained via electrophilic cyclization of

Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

S. Deng et al.

Paper

Synthesis

a trace amount of product was detected using CH₃OH as the

solvent (entry 3). There was a decrease in the yield when

CH₃CN or DMF was used as the solvent (56% and 68%, re-

spectively; entries 4 and 9), while other solvents (EtOAc,

THF, CHCl₃, toluene) all gave good yields (entries 5–8). Con-

sidering the easy operation, DCM was selected as the sol-

vent for subsequent transformations. Furthermore, adding

NBS in batches was also investigated for this transformation

and we found that the yield showed no obvious change (en-

try 10). After screening the conditions carefully, the use of

5.0 equivalents of NBS in DCM under air was selected as the

optimal conditions for this novel transformation (Table 1,

entry 2).

Previous work

(a) Yamamoto's work^10d

R²

I₂, Br₂, ICl, NBS or NIS

CH₃NO₂, argon

R³

N₃

²= H or OAc

(X = I, Br)

(b) Likhar's work^10e

I₂(2.0 equiv)

NaHCO₃(2.0 equiv)

CH₃CN

R^f= C_nF_2n+1

R^f

Table 1 Optimization of the Reaction Conditions^a

NIS (3.0 equiv)

CH₃OH, 60 °C

NBS

(d) Larock's work^11a

I₂, ICl, NIS,

solvent, rt, 10 min

air

NaHCO₃(2.0 equiv)

CH₃CN

(X = I, Br)

2a'

Entry

Halo source (equiv) Solvent

Yield (%)^bof 2a

NBS (2.0 equiv)

1^c

NBS (3.0)

NBS (5.0)

NCS (5.0)

NIS (5.0)

DCM

n.r.

81^f

NaHCO₃(2.0 equiv)

CH₃CN

DCM

This work

CH₃OH

CH₃CN

THF

NBS (5.0 equiv)

DCM, air, 10 min

EtOAc

toluene

CHCl₃

DMF

7^d

Scheme 1 Synthesis of haloquinolines

10^e

12^f

DCM

easily undergo electrophilic substitution reactions in the

presence of NBS. Herein, we report an NBS-mediated cas-

cade electrophilic bromination/cyclization of arylpropar-

gylanilines to form 3,6,8-tribromoquinolines, which can

further undergo the Sonogashira coupling reaction at posi-

tion C-6 regioselectively. Compared with Larock’s method,

our developed strategy has the merit of multibromination,

simple operation and no additional base.

DCM

^aReaction conditions: 1a (0.2 mmol), solvent (2.0 mL), rt, air atmosphere.

^bIsolated yields.

^c2a′ was obtained in 46% yield.

^d15 min.

^eNBS was added in batches.

^f3-Iodo-4-phenylquinoline was obtained.

Initially, N-(3-phenylprop-2-ynyl)aniline (1a) was cho-

sen as the model substrate (Table 1). The desired product 2a

was obtained in 32% yield in the presence of NBS (3.0 equiv)

in DCM (Table 1, entry 1). The structure of 2a was unambig-

uously confirmed by X-ray crystallography.¹⁴Moreover, an-

other compound, 2,4-dibromo-N-(3-phenylprop-2-ynyl)-

aniline (2a′), was also isolated in 46% yield, which indicated

that electrophilic bromination of the aromatic ring is pre-

ferred to cyclization. Compound 2a′ disappeared when the

amount of NBS was increased to 5.0 equivalents, and the

desired product 2a was obtained in 84% yield (entry 2).

Next, some representative solvents, such as CHCl₃, CH₃CN,

EtOAc, THF, CH₃OH, DMF and toluene, were screened. Only

With the optimal reaction conditions in hand, we next

carried out the reactions of a variety of N-(3-phenylprop-2-

ynyl)anilines 1 to investigate the substrate scope (Scheme

2). The corresponding products 2 were obtained in moder-

ate to good yields within 10 minutes despite 1 bearing elec-

tron-rich, electron-neutral or electron-poor substituents

(CH₃, OCH₃, Cl, F, Br, CF₃, CHO, COOEt, CN, phenyl) on the

benzene ring. For substrates having a substituent at the

para-position of the benzene ring, the corresponding prod-

ucts 2b–2i were obtained in 41–81% yield. Unfortunately,

the desired product 2j could not be observed, only an un-

known complex mixture, when using nitro-substituted 1j

S. Deng et al.

Paper

Synthesis

thermore, substrates containing substituents on the aniline

(CH₃, Cl, CF₃; 1r–1t) were also employed and provided the

corresponding products 2r–2t in 65–95% yield. When N-

methyl-substituted propargylaniline 1u was tested, the de-

sired product 2u was obtained in 78% yield. The structure of

2u was also unambiguously confirmed by X-ray crystallog-

raphy.¹⁴

(R) Br

(R) H

NBS (5.0 equiv)

DCM, air, 10 min

2a, R¹= H, 84%

2b, R¹= Cl, 81%

R¹

In order to elucidate the reaction mechanism, we revis-

ited the optimization process as shown in Table 1. When 3.0

equivalents of NBS were added, products 2a and 2a′ were

obtained simultaneously, while compound 2a′ disappeared

when adding 5.0 equivalents of NBS. These results indicated

that the bromination of the benzene ring should occur be-

fore the ring closure, and 2a′ may be the key intermediate

for this reaction. In order to verify this process, 2a′ was iso-

lated and subjected to 3.0 equivalents of NBS in DCM. The

desired product 2a was obtained in 86% yield (Scheme 3a).

When 4-phenylquinoline (3) was treated under the optimal

conditions, bromination did not occur at any position of the

quinoline (Scheme 3b). This result proved that undertaking

the direct bromination of quinoline is difficult because of

its electron deficiency. Furthermore, control experiments

were also conducted under argon atmosphere, oxygen at-

mosphere or dark conditions. There was no obvious change

in the yield of 2a under these conditions (Scheme 3c). These

results indicated that a radical process and oxygen might

not be involved in this reaction.

2c, R¹= CH₃, 73%

2d, R¹= CN, 63%

2e, R¹= CHO, 68%

2f, R¹= CF₃, 69%

2g, R¹= OCH₃, 41%

2h, R¹= Ph, 45%

2i, R¹= COOEt, 65%

2j, R¹= NO₂, trace

OCH₃

2k, 51%

2l, 87%

2m, 61%

2n, 83%

2o, 87%

2p, 78%

NBS (3.0 equiv)

(a)

DCM, rt

86%

2a’

2s, 86%

2r, 95%

2q, 41%

NBS (3.0 equiv)

DCM, rt

no bromination product

(b)

(c)

F₃C

NBS (5.0 equiv)

DCM, rt

CH₃

Br^–

under argon, 83%

under oxygen, 76%

in the dark, 81%

2u, 78%

2t, 65%

Scheme 3 Control experiments

Scheme 2 NBS-mediated bromination and cascade cyclization to

3,6,8-tribromo-4-phenylquinolines 2. Reagents and conditions: 1 (0.2

mmol), DCM (2.0 mL), rt, air atmosphere; isolated yields.

Based on literature reports and the above experiments,

a possible reaction mechanism is proposed as shown in

Scheme 4. Initially, the benzene ring is prone to undergo

electrophilic substitution due to the presence of the amino

group. Heterolysis of the N–Br bond of NBS forms Br⁺as an

electrophile, which then attacks the aromatic ring to give

the intermediate 2,4-dibromo-N-(3-phenylprop-2-ynyl)an-

iline (2a′). The benzene ring is deactivated by the electron-

withdrawing action of two bromine atoms. Subsequently,

2a′ undergoes 6-endo-dig electrophilic bromocyclization to

as the substrate. For substrates with ortho-, meta- or disub-

stitution (3,5-dimethyl, 3,5-dichloro, 2-bromo-4-fluoro;

1n–1p) on the aromatic ring, the corresponding products

2k–2p were obtained in 51–87% yield. When compound 1q

was used as the substrate, 3,6-dibromo-4-(5-methylthio-

phen-2-yl)quinoline (2q) was afforded in 41% yield, sug-

gesting that the alkyne was more likely to be attacked due

to the electron-donating effect of the thiophene group. Fur-

S. Deng et al.

Paper

Synthesis

form intermediate B, followed by deprotonation to give in-

termediate C. Finally, the desired product 2a is obtained by

oxidative aromatization in the presence of NBS.

NBS (5.0 equiv)

(a)

DCM, air, 10 min

81%

without

1a, 1.0 g (4.83 mmol)

column chromatography

2a, 1.73 g

NBS

electrophilic

bromination

(1.2 equiv)

CuI (10 mol%)

Pd(PPh₃)₂Cl₂(5 mol%)

2a'

(b)

2.0 equiv NBS, 2a', 61%; 2a, 15%

3.0 equiv NBS, 2a', 46%; 2a, 32%

5.0 equiv NBS, 2a', trace; 2a, 84%

electrophilic

cyclization

THF

71%

– H⁺

NBS

oxidation

deprotonation

ArB(OH)₂(2.0 equiv)

Ar = p-MeC₆H₄

Pd(OAc)₂(5 mol%)

L1 (10 mol%)

Scheme 4 Proposed reaction mechanism

K₃PO₄(2.0 equiv)

toluene, 110 °C, 12 h

Notably, an obvious advantage of our developed ap-

proach is that this reaction could be scaled up to gram

quantities under the optimal reaction conditions, and the

corresponding product 2a was obtained in 81% yield

(Scheme 5). Importantly, product 2a can be precipitated out

of solution without column chromatography, which might

51%

Scheme 5 Gram-scale synthesis of 2a and its cross-coupling derivat-

ization

provide

a potential application in organic synthesis

(Scheme 5a). Furthermore, the synthetic application of the

3,6,8-tribromo-4-phenylquinolines was demonstrated by

palladium-catalyzed cross-coupling reactions (Scheme 5b).

Firstly, product 2a underwent Sonogashira coupling with

phenylacetylene to give product 4 in a highly regioselective

way in 71% yield. Moreover, the Suzuki–Miyaura coupling

of 4 with arylboronic acid also smoothly proceeded to give

the corresponding product 5 in moderate yield (Scheme

5b).

2,4-Dibromo-N-(3-phenylprop-2-ynyl)aniline (2a′); Typical Proce-

dure for Electrophilic Bromination

NBS (70.8 mg, 0.4 mmol) was added to a stirred solution of 1a (41.4

mg, 0.2 mmol) in DCM (2 mL). The resulting mixture was stirred at rt

for 10 min and the progress of the reaction was monitored by TLC. Af-

ter completion of the reaction, the reaction mixture was diluted and

extracted with DCM (3 × 5 mL). The combined organic layer was dried

over anhydrous Na₂SO₄and concentrated under reduced pressure.

The crude product was purified by column chromatography on silica

gel to give the corresponding product 2a′.

In conclusion, we have developed a novel and efficient

NBS-mediated cascade bromination/cyclization of N-(3-

phenylprop-2-ynyl)anilines. The reaction can be completed

in a few minutes to obtain a series of 3,6,8-tribromoquino-

line compounds under mild conditions. The obtained multi-

bromoquinoline products could then smoothly undergo the

Sonogashira reaction at position C-6 in a highly regioselec-

tive way. Further application to construct a corresponding

library of quinolines is under way in our laboratory.

Yellow solid; yield: 44.5 mg (61%); mp 55–56 °C.

IR (KBr): 3041, 2921, 2847, 1666, 1588, 1499, 1385, 1310, 1082, 1034,

867, 799, 757, 692, 538 cm^–1

¹H NMR (400 MHz, CD₂Cl₂):  = 7.59 (d, J = 2.0 Hz, 1 H), 7.41–7.30 (m,

6 H), 6.76 (d, J = 8.8 Hz, 1 H), 4.72 (s, 1 H), 4.22 (d, J = 4.4 Hz, 2 H).

¹³C NMR (100 MHz, CD₂Cl₂):  = 143.9, 134.8, 132.1, 131.6, 128.9,

128.8, 123.0, 113.7, 110.8, 109.5, 85.7, 83.8, 34.7.

HRMS (EI): m/z [M + H]⁺calcd for C₁₅H₁₂Br₂N: 363.9331; found:

363.9334.

Cascade Electrophilic Bromination/Cyclization Reaction; General

Procedure

All reagents were purchased from commercial sources and used with-

out further treatment, unless otherwise indicated. Dichloromethane

(DCM) was purchased from Adamas Company (safe-dry, water <50

ppm). ¹H and ¹³C NMR spectra were recorded on Bruker 400 MHz

spectrometers; chemical shifts are given in parts per million (ppm)

NBS (177.0 mg, 1.0 mmol) was added to a stirred solution of 1a–1u

(0.2 mmol) in DCM (2 mL). The resulting mixture was stirred at rt for

10 min and the progress of the reaction was monitored by TLC. After

completion of the reaction, the reaction mixture was diluted and ex-

tracted with DCM (3 × 5 mL). The combined organic layer was dried

over anhydrous Na₂SO₄and concentrated under reduced pressure.

The crude product was purified by column chromatography on silica

gel to give the corresponding product 2a–2u.

relative to standard tetramethylsilane (0.00 ppm for H NMR) or re-

sidual solvent peaks for ¹³C NMR. HRMS was obtained using aQ-TOF

instrument equipped with an ESI source. Standard column chroma-

tography was performed on 200–300 mesh silica gel using flash col-

umn chromatography techniques.

S. Deng et al.

Paper

Synthesis

3,6,8-Tribromo-4-phenylquinoline (2a)

3,6,8-Tribromo-4-(4-(trifluoromethyl)phenyl)quinoline (2f)

White solid; yield: 74.2 mg (84%); mp 196–197 °C.

Yellow solid; yield: 70.4 mg (69%); mp 212–213 °C.

IR (KBr): 3045, 1890, 1584, 1461, 1345, 1112, 1082, 1032, 983, 853,

IR (KBr): 3073, 1620, 1584, 1465, 1382, 1327, 1267, 1219, 1165, 1125,

762, 700, 667, 614 cm^–1

1069, 1022, 988, 790, 744, 626, 528 cm^–1

¹H NMR (400 MHz, CDCl₃):  = 9.15 (s, 1 H), 8.15 (s, 1 H), 7.60–7.57

(m, 4 H), 7.28 (d, J = 5.6 Hz, 2 H).

¹H NMR (400 MHz, CDCl₃):  = 9.15 (s, 1 H), 8.18 (s, 1 H), 7.86 (d, J =

8.0 Hz, 2 H), 7.49 (s, 1 H), 7.44 (d, J = 8.0 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃):  = 153.0, 147.5, 142.8, 136.1, 135.7,

130.7, 129.3, 129.2, 128.9, 128.4, 126.1, 121.3, 120.7.

HRMS (EI): m/z [M + H]⁺calcd for C₁₅H₉Br₃N: 439.8280; found:

439.8286.

¹³C NMR (100 MHz, CDCl₃):  = 152.9, 145.7, 142.9, 139.4, 136.4, 131.4

(q, ²J = 32.5 Hz), 130.1, 129.8, 127.7, 126.5, 126.0 (q, ³J = 3.2 Hz), 123.8

(q, ¹J = 270.7 Hz), 121.7, 120.5.

HRMS (EI): m/z [M + H]⁺calcd for C₁₆H₈Br₃F₃N: 507.8153; found:

507.8155.

3,6,8-Tribromo-4-(4-chlorophenyl)quinoline (2b)

3,6,8-Tribromo-4-(4-methoxyphenyl)quinoline (2g)

White solid; yield: 38.7 mg (41%); mp 190–191 °C.

White solid; yield: 77.2 mg (81%); mp 163–164 °C.

IR (KBr): 3039, 1721, 1597, 1579, 1490, 1461, 1347, 1112, 1084, 1016,

984, 859, 820, 770, 613, 524, 482 cm^–1

IR (KBr): 3033, 2933, 1609, 1583, 1509, 1459, 1346, 1290, 1247, 1176,

1111, 1027, 985, 868, 826, 798, 735, 613 cm^–1

¹H NMR (400 MHz, DMSO-d₆):  = 9.26 (s, 1 H), 8.43 (s, 1 H), 7.70 (d,

J = 6.4 Hz, 2 H), 7.48–7.45 (m, 3 H).

¹H NMR (400 MHz, CDCl₃):  = 9.13 (s, 1 H), 8.15 (d, J = 2.4 Hz, 1 H),

7.66 (s, 1 H), 7.22 (d, J = 8.4 Hz, 2 H), 7.09 (d, J = 8.8 Hz, 2 H), 3.93 (s, 3

H).

¹³C NMR (100 MHz, CDCl₃):  = 160.2, 153.0, 147.3, 143.0, 136.0,

131.1, 130.6, 128.5, 127.8, 126.1, 121.2, 121.1, 114.3, 55.4.

¹³C NMR (100 MHz, DMSO-d₆):  = 153.2, 146.0, 142.3, 135.8, 134.4,

134.3, 131.3, 130.2, 129.3, 127.9, 126.4, 121.1, 120.9.

HRMS (EI): m/z [M + H]⁺calcd for C₁₅H₈Br₃ClN: 473.7890; found:

473.7896.

HRMS (EI): m/z [M + H]⁺calcd for C₁₆H₁₁Br₃NO: 469.8353; found:

469.8348.

3,6,8-Tribromo-4-p-tolylquinoline (2c)

White solid; yield: 66.6 mg (73%); mp 142–144 °C.

4-([1,1′-Biphenyl]-4-yl)-3,6,8-tribromoquinoline (2h)

Yellow solid; yield: 46.6 mg (45%); mp 195–196 °C.

IR (KBr): 2918, 1721, 1597, 1579, 1490, 1461, 1347, 1112, 1084, 1016,

984, 859, 820, 770, 613, 524, 482 cm^–1

IR (KBr): 3070, 1938, 1640, 1579, 1457, 1402, 1343, 1107, 1088, 981,

¹H NMR (400 MHz, DMSO-d₆):  = 9.24 (s, 1 H), 8.41 (s, 1 H), 7.48 (s, 1

H), 7.43 (d, J = 6.0 Hz, 2 H), 7.28 (d, J = 6.4 Hz, 2 H), 2.45 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d₆):  = 153.3, 147.2, 142.4, 139.0, 135.7,

132.6, 130.5, 129.7, 129.2, 128.1, 126.3, 120.9, 120.8, 21.2.

HRMS (EI): m/z [M + H]⁺calcd for C₁₆H₁₁Br₃N: 453.8436; found:

937, 849, 765, 734, 722, 692, 613, 522 cm^–1

¹H NMR (400 MHz, CDCl₃):  = 9.16 (s, 1 H), 8.17 (s, 1 H), 7.80 (d, J =

8.0 Hz, 2 H), 7.73–7.69 (m, 3 H), 7.51 (t, J = 7.6 Hz, 2 H), 7.44–7.36 (m,

3 H).

¹³C NMR (100 MHz, CDCl₃):  = 153.0, 147.1, 142.9, 142.0, 140.1,

136.1, 134.5, 130.7, 129.7, 129.0, 128.4, 127.9, 127.5, 127.2, 126.2,

121.3, 120.8.

453.8437.

4-(3,6,8-Tribromoquinolin-4-yl)benzonitrile (2d)

HRMS (EI): m/z [M + H]⁺calcd for C₂₁H₁₃Br₃N: 515.8593; found:

515.8596.

Yellow solid; yield: 58.8 mg (63%); mp 263–265 °C.

IR (KBr): 3068, 3035, 2226, 1928, 1640, 1581, 1463, 1387, 1349, 1266,

1216, 1114, 1084, 983, 899, 869, 832, 791, 718, 615, 580, 528 cm^–1

Ethyl 4-(3,6,8-Tribromoquinolin-4-yl)benzoate (2i)

Yellow solid; yield: 66.8 mg (65%); mp 185–186 °C.

¹H NMR (400 MHz, CDCl₃):  = 9.16 (s, 1 H), 8.19 (d, J = 2.0 Hz, 1 H),

7.90 (d, J = 7.6 Hz, 2 H), 7.45–7.43 (m, 3 H).

¹³C NMR (100 MHz, CDCl₃):  = 152.9, 145.1, 142.9, 140.3, 136.5,

132.8, 130.2, 129.8, 127.5, 126.6, 121.9, 120.2, 118.1, 113.5.

HRMS (EI): m/z [M + H]⁺calcd for C₁₆H₈Br₃N₂: 464.8232; found:

IR (KBr): 3076, 2980, 2900, 1716, 1583, 1464, 1402, 1349, 1282, 1180,

1111, 1023, 988, 898, 863, 766, 710, 683, 616, 570, 527 cm^–1

¹H NMR (400 MHz, CDCl₃):  = 9.13 (s, 1 H), 8.25 (d, J = 8.4 Hz, 2 H),

8.15 (d, J = 2.4 Hz, 1 H), 7.49 (d, J = 2.0 Hz, 1 H), 7.38 (d, J = 8.4 Hz, 2 H),

4.45 (q, J = 7.2 Hz, 2 H), 1.44 (t, J = 7.2 Hz, 3 H).

464.8235.

¹³C NMR (100 MHz, CDCl₃):  = 165.9, 152.8, 146.3, 142.8, 140.1, 136.2

× 2, 131.3, 130.1, 129.3, 127.9, 126.3, 121.6, 120.3, 61.4, 14.4.

HRMS (EI): m/z [M + H]⁺calcd for C₁₈H₁₃Br₃NO₂: 511.8491; found:

511.8493.

4-(3,6,8-Tribromoquinolin-4-yl)benzaldehyde (2e)

White solid; yield: 63.9 mg (68%); mp 198–199 °C.

IR (KBr): 3061, 1701, 1639, 1464, 1351, 1207, 1115, 988, 751, 616 cm^–1

¹H NMR (400 MHz, DMSO-d₆):  = 10.15 (s, 1 H), 9.29 (s, 1 H), 8.45 (s,

1 H), 8.15 (d, J = 7.6 Hz, 2 H), 7.66 (d, J = 8.0 Hz, 2 H), 7.42 (s, 1 H).

¹³C NMR (100 MHz, DMSO-d₆):  = 193.1, 153.2, 146.1, 142.3, 141.4,

3,6,8-Tribromo-4-(3-methoxyphenyl)quinoline (2k)

White solid; yield: 48.1 mg (51%); mp 170–171 °C.

136.7, 135.9, 130.3, 130.2, 129.8, 127.8, 126.4, 121.2, 120.4.

HRMS (EI): m/z [M + H]⁺calcd for C₁₆H₉Br₃NO: 467.8229; found:

467.8229.

IR (KBr): 3081, 2990, 2831, 1845, 1608, 1581, 1463, 1430, 1380, 1346,

1288, 1219, 1162, 1114, 1053, 1002, 865, 782, 736, 707, 667, 643, 563

cm^–1

S. Deng et al.

Paper

Synthesis

¹H NMR (400 MHz, CDCl₃):  = 9.13 (s, 1 H), 8.15 (s, 1 H), 7.62 (s, 1 H),

7.49 (t, J = 8.0 Hz, 1 H), 7.08 (d, J = 5.6 Hz, 1 H), 6.84 (d, J = 7.6 Hz, 1 H),

6.80 (s, 1 H), 3.87 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃):  = 159.8, 152.9, 147.2, 142.8, 137.0,

136.1, 130.6, 130.1, 128.4, 126.1, 121.3, 121.2, 120.6, 114.8, 114.6,

55.4.

3,6,8-Tribromo-4-(2-bromo-4-fluorophenyl)quinoline (2p)

Yellow solid; yield: 84.1 mg (78%); mp 180–181 °C.

IR (KBr): 3076, 1588, 1489, 1460, 1384, 1349, 1261, 1205, 1114, 1085,

1040, 988, 943, 866, 821, 746, 652, 615, 557, 525 cm^–1

¹H NMR (400 MHz, CDCl₃):  = 9.23 (s, 1 H), 8.25 (s, 1 H), 7.64–7.62

(m, 1 H), 7.47 (s, 1 H), 7.37–7.28 (m, 2 H).

HRMS (EI): m/z [M + H]⁺calcd for C₁₆H₁₁Br₃NO: 469.8385; found:

469.8388.

¹³C NMR (100 MHz, CDCl₃):  = 162.9 (d, J = 252.6 Hz), 152.9, 145.4,

142.8, 136.3, 132.9 (d, ⁴J = 3.7 Hz), 131.7 (d, ³J = 8.6 Hz), 130.0, 127.4,

126.5, 123.3 (d, ³J = 9.7 Hz), 121.8, 121.5, 120.9 (d, ²J = 24.5 Hz), 115.6

(d, ²J = 21.5 Hz).

3,6,8-Tribromo-4-(2-fluorophenyl)quinoline (2l)

White solid; yield: 80.0 mg (87%); mp 210–211 °C.

HRMS (EI): m/z [M + H]⁺calcd for C₁₅H₇Br₄FN: 535.7291; found:

IR (KBr): 3075, 3042, 1881, 1616, 1585, 1462, 1385, 1350, 1246, 1217,

535.7293.

1096, 989, 892, 860, 815, 763, 665, 616, 532 cm^–1

¹H NMR (400 MHz, CDCl₃):  = 9.18 (s, 1 H), 8.19 (s, 1 H), 7.63–7.58

(m, 2 H), 7.40 (t, J = 7.6 Hz, 1 H), 7.35–7.28 (m, 2 H).

3,6-Dibromo-4-(5-methylthiophen-2-yl)quinoline (2q)

Yellow solid; yield: 31.4 mg (41%); mp 144–145 °C.

¹³C NMR (100 MHz, CDCl₃):  = 159.3 (d, J = 248.0 Hz), 152.8, 142.8,

IR (KBr): 3160, 3080, 2954, 1774, 1700, 1370, 1295, 1190, 1114, 1060,

141.9, 136.2, 131.7, 131.3 (d, ³J = 7.8 Hz), 130.4, 127.7, 126.4, 124.7,

123.3 (d, ²J = 15.6 Hz), 121.7, 121.6, 116.5 (d, ²J = 20.8 Hz).

1004, 934, 848, 822, 643, 558 cm^–1

¹H NMR (400 MHz, DMSO-d₆):  = 9.13 (s, 1 H), 8.04 (d, J = 8.8 Hz, 1

H), 7.96 (d, J = 8.0 Hz, 1 H), 7.78 (s, 1 H), 7.10 (d, J = 3.6 Hz, 1 H), 7.02

(d, J = 4.0 Hz, 1 H), 2.57 (s, 3 H).

HRMS (EI): m/z [M + H]⁺calcd for C₁₅H₈Br₃FN: 457.8185; found:

457.8176.

¹³C NMR (100 MHz, DMSO-d₆):  = 152.5, 145.1, 142.8, 140.1, 133.4,

132.1, 131.8, 130.4, 130.1, 127.7, 126.4, 121.8, 121.2, 15.1.

HRMS (EI): m/z [M + H]⁺calcd for C₁₄H₁₀Br₂NS: 381.8895; found:

3,6,8-Tribromo-4-(naphthalen-1-yl)quinoline (2m)

Yellow solid; yield: 60.0 mg (61%); mp 218–219 °C.

IR (KBr): 3041, 1639, 1581, 1384, 1345, 1271, 1213, 1159, 1125, 1084,

381.8896.

1045, 1014, 950, 861, 796, 773, 728, 651 cm^–1

¹H NMR (400 MHz, CDCl₃):  = 9.22 (s, 1 H), 8.16 (s, 1 H), 8.07 (d, J =

8.4 Hz, 1 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.68–7.65 (m, 1 H), 7.56 (t, J = 7.2

Hz, 1 H), 7.41–7.34 (m, 3 H), 7.10 (d, J = 7.2 Hz, 1 H).

¹³C NMR (100 MHz, CDCl₃):  = 153.0, 146.4, 142.9, 136.3, 133.7,

133.4, 131.3, 130.7, 129.8, 128.8, 128.4, 127.3, 127.2, 126.7, 126.2,

125.5, 124.9, 122.1, 121.5.

3,8-Dibromo-6-methyl-4-phenylquinoline (2r)

Yellow solid; yield: 71.6 mg (95%); mp 113–115 °C.

IR (KBr): 3051, 2909, 1615, 1473, 1363, 1159, 1114, 1076, 1037, 994,

931, 856, 766, 735, 702, 631, 528 cm^–1

¹H NMR (400 MHz, CDCl₃):  = 9.08 (s, 1 H), 7.90 (s, 1 H), 7.57–7.54

(m, 3 H), 7.30–7.27 (m, 2 H), 7.19 (s, 1 H), 2.39 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃):  = 151.7, 147.4, 142.6, 138.3, 136.7,

135.3, 130.0, 129.2, 128.8, 128.7, 125.2, 124.6, 119.8, 21.5.

HRMS (EI): m/z [M + H]⁺calcd for C₁₉H₁₁Br₃N: 489.8436; found:

489.8439.

HRMS (EI): m/z [M + H]⁺calcd for C₁₆H₁₂Br₂N: 375.9331; found:

375.9335.

3,6,8-Tribromo-4-(3,5-dimethylphenyl)quinoline (2n)

Yellow solid; yield: 78.0 mg (83%); mp 153–154 °C.

IR (KBr): 3058, 2912, 1918, 1637, 1603, 1461, 1353, 1289, 1222, 1120,

3,8-Dibromo-6-chloro-4-phenylquinoline (2s)

1087, 1043, 856, 696, 627, 521 cm^–1

Yellow solid; yield: 68.4 mg (86%); mp 170–171 °C.

¹H NMR (400 MHz, DMSO-d₆):  = 9.23 (s, 1 H), 8.40 (s, 1 H), 7.46 (s, 1

H), 7.21 (s, 1 H), 6.97 (s, 2 H), 2.37 (s, 6 H).

¹³C NMR (100 MHz, DMSO-d₆):  = 153.2, 147.4, 142.3, 138.3, 135.7,

135.5, 130.8, 130.4, 128.1, 126.6, 126.3, 120.8, 120.7, 21.1.

HRMS (EI): m/z [M + H]⁺calcd for C₁₇H₁₃Br₃N: 467.8593; found:

467.8596.

IR (KBr): 3045, 1698, 1597, 1546, 1462, 1444, 1387, 1353, 1115, 1094,

1035, 902, 856, 795, 769, 763, 689, 625, 572, 533 cm^–1

¹H NMR (400 MHz, CDCl₃):  = 9.13 (s, 1 H), 8.01 (s, 1 H), 7.58–7.56

(m, 3 H), 7.43 (s, 1 H), 7.28 (d, J = 6.4 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃):  = 152.9, 147.4, 142.6, 135.7, 133.6,

133.3, 130.1, 129.2, 129.1, 128.9, 126.0, 125.0, 120.7.

HRMS (EI): m/z [M + H]⁺calcd for C₁₅H₉Br₂ClN: 395.8785; found:

395.8786.

3,6,8-Tribromo-4-(3,5-dichlorophenyl)quinoline (2o)

White solid; yield: 88.9 mg (87%); mp 204–205 °C.

IR (KBr): 3075, 2912, 1637, 1586, 1561, 1435, 1385, 1342, 1119, 1092,

3,8-Dibromo-4-phenyl-6-(trifluoromethyl)quinoline (2t)

White solid; yield: 56.0 mg (65%); mp 178–179 °C.

1019, 865, 787, 675 cm^–1

¹H NMR (400 MHz, CDCl₃):  = 9.14 (s, 1 H), 8.19 (s, 1 H), 7.57 (s, 1 H),

7.52 (s, 1 H), 7.18 (s, 2 H).

¹³C NMR (100 MHz, CDCl₃):  = 152.8, 144.4, 142.8, 138.5, 136.5,

135.9, 129.9, 129.6, 127.6, 126.5, 121.9, 120.6.

IR (KBr): 3052, 2930, 1477, 1438, 1407, 1368, 1295, 1166, 1124, 1084,

1034, 990, 883, 798, 764, 699, 655, 606 cm^–1

¹H NMR (400 MHz, CDCl₃):  = 9.26 (s, 1 H), 8.23 (s, 1 H), 7.76 (s, 1 H),

7.60–7.59 (m, 3 H), 7.30–7.29 (m, 2 H).

HRMS (EI): m/z [M + H]⁺calcd for C₁₅H₇Br₃Cl₂N: 507.7500; found:

507.7510.

S. Deng et al.

Paper

Synthesis

¹³C NMR (100 MHz, CDCl₃):  = 154.8, 149.2, 145.1, 135.4, 129.6 (q,

²J = 33.1 Hz), 129.5, 129.1, 129.0 × 2, 126.5, 124.1 (q, ³J = 4.1 Hz),

124.0, 122.8 (q, ¹J = 271.6 Hz), 121.2.

HRMS (EI): m/z [M + H]⁺calcd for C₁₆H₉Br₂F₃N: 429.9048; found:

429.9053.

placed in a pressure tube. Toluene (2 mL) was added, and the mixture

was stirred at 110 °C for 12 h. After the mixture was cooled to rt, the

reaction mixture was quenched with water, and the product was ex-

tracted three times with EtOAc. The combined organic layer was dried

over anhydrous Na₂SO₄. The residue obtained after evaporation of the

solvent was purified by silica gel column chromatography (4% EtOAc

in petroleum ether) to afford 5.

3,6-Dibromo-1-methyl-4-phenylquinolin-1-ium bromide (2u)

Yellow solid; yield: 71.4 mg (78%); mp >300 °C.

White solid; yield: 44.6 mg (51%); mp 65–67 °C.

IR (KBr): 3025, 2915, 1640, 1480, 1187, 1116, 1026, 882, 826, 757,

IR (KBr): 3650, 3310, 3090, 3052, 1605, 1556, 1513, 1366, 1319, 1259,

698, 606 cm^–1

1165, 1134, 1077, 1036, 949, 881, 840, 754, 707, 616, 517 cm^–1

¹H NMR (400 MHz, CDCl₃):  = 8.99 (d, J = 2.0 Hz, 1 H), 7.82 (s, 2 H),

7.64 (d, J = 6.4 Hz, 2 H), 7.52–7.51 (m, 2 H), 7.40–7.39 (m, 3 H), 7.35–

7.33 (m, 5 H), 7.26–7.24 (m, 2 H), 7.04 (s, 4 H), 2.45 (s, 3 H), 2.30 (s, 3

H).

¹³C NMR (100 MHz, CDCl₃):  = 152.1, 145.1, 144.9, 141.3, 137.4,

136.9, 136.5, 136.2, 135.0, 133.4, 132.3, 131.7, 130.6, 130.5, 129.9,

129.1, 128.9, 128.5, 128.4, 128.3 × 2, 127.8, 127.7, 123.0, 121.4, 90.4,

89.6, 21.3, 21.1.

¹H NMR (400 MHz, DMSO-d₆):  = 10.14 (s, 1 H), 8.55 (d, J = 9.6 Hz, 1

H), 8.49–8.46 (m, 1 H), 7.72 (d, J = 6.8 Hz, 4 H), 7.47–7.44 (m, 2 H),

4.70 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d₆):  = 156.4, 152.3, 137.7, 136.8, 133.9,

130.6, 130.3, 129.8, 129.4, 128.8, 124.6, 122.2, 118.3, 45.7.

HRMS (EI): m/z [M – Br]⁺calcd for C₁₆H₁₂Br₂N: 375.9331; found:

375.9328.

HRMS (EI): m/z [M + H]⁺calcd for C₃₇H₂₈N: 486.2216; found:

486.2217.

Gram-Scale Synthesis of 2a

NBS (4.27 g, 24.0 mmol) was added in one portion to a stirred solu-

tion of 1a (1.0 g, 4.8 mmol) in DCM (20 mL). The resulting mixture

was stirred at rt for 10 min under air atmosphere and the progress of

the reaction was monitored by TLC. After completion, product 2a pre-

cipitates out of the reaction mixture, and was then filtered, washed

with water and dried in an oven to give 2a as a white solid; yield: 1.73

g (81%).

Conflict of Interest

The authors declare no conflict of interest.

Funding Information

We acknowledge the National Natural Science Foundation of China

(No. 21676131, No. 21462019, and No. 22001101), the Natural Sci-

ence Foundation of Jiangxi Province (20181BAB203005 and

20143ACB20012), and the Education Department of Jiangxi Province

3,8-Dibromo-4-phenyl-6-(phenylethynyl)quinoline (4)

Under argon atmosphere, 3,6,8-tribromo-4-phenylquinoline (2a;

0.703 g, 1.59 mmol), phenylacetylene (0.135 g, 1.33 mmol), CuI (0.025

g, 0.13 mmol) and bis(triphenylphosphine)palladium chloride (0.046

g, 0.066 mmol) were placed in a reaction flask. THF (20 mL) and Et₃N

(7 mL) were added, and the mixture was stirred at 50 °C for 12 h. After

that, phenylacetylene (0.135 g per time) was injected into the reac-

tion solution at 12 h intervals until the starting material 2a was con-

sumed. After completion of the reaction, the reaction mixture was

concentrated, and diluted and extracted with DCM. The combined or-

ganic layer was dried over anhydrous Na₂SO₄and concentrated under

reduced pressure. The crude product was purified by column chroma-

tography on silica gel to give the corresponding product 4 (TLC; 2%

EtOAc in petroleum ether).

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Supporting Information

Supporting information for this article is available online at

https://doi.org/10.1055/a-1396-8198. Su

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Yellow solid; yield: 522.9 mg (71%); mp 191–192 °C.

IR (KBr): 3056, 2207, 1601, 1491, 1464, 1443, 1361, 1177, 1133, 1105,

940, 876, 755, 697, 630, 591 cm^–1

¹H NMR (400 MHz, CDCl₃):  = 9.14 (s, 1 H), 8.18 (s, 1 H), 7.59 (d, J =

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contain the supplementary crystallographic data for this paper.

The data can be obtained free of charge from The Cambridge

Crystallographic Data Centre via www.ccdc.cam.ac.uk/struc-

tures.

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