Directing Group Enables Electrochemical Selectively Meta-Bromination of Pyridines under Mild Conditions

Bromination of Pyridines under Mild Conditions

Note

Directing Group Enables Electrochemical Selectively Meta-

Yanwei Wu, Shanghui Xu, Hong Wang, Dongxu Shao, Qiqi Qi, Yi Lu, Li Ma, Jianhua Zhou, Wei Hu,

Wei Gao,* and Jianbin Chen*

Cite This: https://doi.org/10.1021/acs.joc.1c00923

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sı Supporting Information

ABSTRACT: Without the use of catalysts and oxidants, a facile

and sustainable electrochemical bromination protocol was

developed. By introducing the directing groups, the regioselectivity

of pyridine derivatives could be controlled at the meta-position

utilizing the inexpensive and safe bromine salts at room

temperature. A variety of brominated pyridine derivatives were

obtained in 28−95% yields, and the reaction could be readily

performed at a gram scale. By combining the installation and removing the directing group, the concept of meta-bromination of

pyridines could be veriﬁed.

yridines are one of the privileged scaﬀolds which are

Scheme 2. Classic and Our Strategy for the Meta-

Bromination of Pyridine

frequently encountered in biologically active molecules

and pharmaceuticals (Scheme 1). Therefore, the development

Scheme 1. Representative Pharmaceuticals Containing

Pyridine Motifs

of reliable functionalization approaches for pyridine derivatives

has always been attractive to synthetic scientists. Because of

their inherently electron-deﬁcient nature, pyridines displayed

extremely low reactivities in aromatic electrophilic substitution

group: ﬁrst, it should have a strong electron-donating ability;

second, it should be easily installed and removed; third, it

should be stable and will not interrupt the desired trans-

formation. With these points in mind, the amino group stands

out because the amination of pyridines by sodium amide

(

S_EAr) reactions. For instance, the traditional procedure for

the bromination of pyridines required harsh conditions

(

greater than 300 °C) with toxic, corrosive, and volatile

bromine (Scheme 2, upper). To overcome this disadvantage,

we envision taking advantage of the umpolung strategy to

(

NaNH ) was well established by Chichibabin and co-workers

achieve the bromination of pyridine derivatives under mild

conditions. Speciﬁcally, installation of the electron-donating

group as the directing group would remarkably enhance the

nucleophilicity of the C3 position of the pyridines followed by

the bromination and removal of the directing group might

provide the targeted product under mild conditions (Scheme

Special Issue: Electrochemistry in Synthetic Organic

Chemistry

Received: April 20, 2021

, bottom). However, there are some criteria for the directing

XXXX American Chemical Society

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Note

in 1914. Considering the smooth removal of the amino

that the electricity was indispensable (Table 1, entry 2).

Notably, electrode materials played a pivotal role as the yield

was signiﬁcantly reduced when Pt served as the anode or RVC

was used as the cathode (Table 1, entries 3 and 4). Increasing

the current resulted in a slight reducing of the yield, whereas

decreasing the current improves the yield up to 93% (Table 1,

entries 5 and 6). Changing the electrolyte to less polar ones

group, we need to focus on the bromination step of the 2-

aminopyridine derivatives.

It should be noted that electrophilic bromination of 2-

aminopyridines by bromosuccinimide (NBS) and bromine

^B^r2⁾have been developed in the synthetic community.

However, NBS and Br are relatively toxic and unstable.

Interestingly, a series of bromides such as N-methylpyrrolidin-

-one hydrotribromide, 1-butyl-3-methylimidazolium tribro-

(

TBAPF and TBAClO ) suﬀered a signiﬁcantly decreased

6 4

yield (Table 1, entries 7 and 8). Remarkably, the solvent

demonstrated profound inﬂuence as methanol almost shut

down the reaction (although DMA can provide the targeted

mide ([BMIM]Br ), tetrabutylammonium tribromide

(

[TBA]Br ), 1-butylpyridinium bromide, cupric bromide

12 13

(

CuBr₂), and sodium bromide (NaBr) have also been

product in 76% yield ) (Table 1, entries 9 and 10). When

reported as the brominating reagents in the presence of strong

chemical oxidants, such as hydrogen peroxides (H O ), Oxone,

and/or potassium persulfate (K S O ). Nevertheless, the

sodium bromide or lithium bromide was employed as the

bromide source, the product was obtained in 57% and 62%

yield, respectively (Table 1, entries 11 and 12). Unfortunately,

this methodology is not suitable for prepare chloropyridines

and iodopyridines with TBACl and TBAI instead of TBABr,

respectively.

With the optimal conditions in hand, we began to explore

the substrate scope for the newly developed bromination

protocol (Table 2). To our delight, a wide range of electron-

donating groups, such as methyl (10, 11, 12), methoxy (13,

14), and electron-withdrawing groups, taking the ﬂuorine (8,

disadvantages of the aforementioned bromination protocols

are that they utilize toxic, unstable reagents and chemical

oxidants, which results in chemical waste and pollution. Hence,

the development of an economical and environmentally benign

bromination procedure is needed. In the past decades,

electrochemical organic synthesis has witnessed signiﬁcant

progress because one can use clean electricity as the surrogate

for the external oxidants, which remarkably eliminated the

environmental pollution issues. Therefore, we wish to

describe our newly developed electrochemical bromination

protocol for the 2-aminopyridines under catalyst- and oxidant-

), chlorine (2, 3, 4), and bromine (5, 6, 7) as the examples,

Table 2. Substrate Scope for the 2-Aminopyridine

free conditions at room temperature.

Derivatives

To test the proof of concept, we chose the commercially

available 2-aminopyridine as the template substrate. After wide

screening, we obtained the relatively optimal conditions as

follows: lithium perchlorate (LiClO , 0.1 M) as the electrolyte,

tetrabutylammonium bromide (TBABr, 1.5 equiv) as the

bromide source, MeCN/HOAc (8/1 mL) as the mixed

solvent, and RVC and platinum plate as the anode and

cathode, and the reaction was electrolyzed under the constant

current model (5 mA) at room temperature. The desired

product 2-amino-5-bromopyridine 1 (Table 1, entry 1) was

obtained in 86% isolated yield. Control experiments conﬁrmed

Table 1. Optimization of the Reaction Conditions

entry

variation from the standard conditions

yield (%)

no electric current

Pt as anode

RVC as cathode

10 mA, 4 h

trace

2.5 mA, 16 h

BuNPF (0.1 M) as electrolyte

BuNClO (0.1 M) as electrolyte

MeOH (9 mL) as solvent

DMA (8 mL) as solvent

NaBr (2 equiv) instead of TBABr

LiBr (2 equiv) instead of TBABr

Reaction conditions: RVC as anode, Pt as cathode, 5 mA, substance

(0.5 mmol), TBABr (0.75 mmol), LiClO (1.8 equiv, 0.1 M), MeCN

(

0.5 mmol), TBABr (0.75 mmol, 1.5 equiv), LiClO (0.1 M), MeCN

8 mL), HOAc (1 mL), 25 °C, 8 h, N isolated yields. DMA (8 mL),

NaBr (2 equiv), RVC as anode, Ni as cathode, 4 mA, 12 h, 25 °C, air.

(8 mL), HOAc (1 mL), 25 °C, 8 h, N , isolated yields. 2.5 mA, 16 h.

DMA (8 mL), NaBr (2 equiv), RVC as anode, Ni as cathode, 4 mA,

12 h, 25 °C, air. NaBr (0.5 mmol), 5 mA, 6 h. TBABr (1.5 mmol), 5

RVC = reticulated vitreous carbon.

mA, 16 h.

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Note

are tolerated well regardless of the substituted position. In

addition, the strong electron-withdrawing group, for example,

ester, worked smoothly under our conditions (15). However,

the reaction almost shut down when the ester group was

substituted at the para-position. which presumably originated

from the unmatched electron eﬀect and the low solubility in

our system (16). Furthermore, when the meta-position was

preinstalled by the chlorine atom, the bromination selectively

took place at the ortho-position of the amino group in

moderate yield (17). In particular, this scaﬀold played a crucial

role in the construction of the commercialized drug etoricoxib.

Etoricoxib is a nonsteroidal anti-inﬂammatory drug with

cathode, respectively. Under 25 mA constant current

electrolysis for 38 h, the reaction provided the ﬁnal product

smoothly in slightly decreased yield (1.19 g, 69%, Scheme 3,

Scheme 3. Gram-Scale and Diversiﬁcation Reaction

antipyretic, analgesic, and potential antineoplastic properties.

The success of aminopyridine derivates encouraged us to

extend other directing groups (Table 3). The dimethylamino

top). Subsequently, the conversion of the directing group was

Table 3. Extending to Other Electron-Donating Groups for

Pyridine Derivatives

investigated (Scheme 3, bottom). Taking 2-amino-5-bromo-

pyridine as an example,

the tert-butyl nitrite and

triethylbenzylammonium chloride were added to dichloro-

methane at room temperature for 12 h, and the amino group

was replaced with a chloro atom with 77% eﬃciency (26).

To gain insights into the reaction mechanism, we conducted

the radical-trapping experiments. As we can see, the addition of

a radical scavenger, such as TEMPO and BHT, completely

shut down the reaction. Furthermore, in the presence of 1,1-

diphenylethylene, the (2-bromoethene-1,1-diyl)dibenzene 27

was detected by GC−MS, which conﬁrmed that the bromine

radicals were generated during the reaction (Scheme 4). In

Scheme 4. Control Experiments

Reaction conditions: RVC as anode, Pt as cathode, 5 mA, substance

(

0.5 mmol), TBABr (0.75 mmol), LiClO (1.8 equiv, 0.1 M), MeCN

8 mL), HOAc (1 mL), 25 °C, 8 h, N isolated yields. TBABr (0.5

mmol). TBABr (0.5 mmol), 6 h. 7 h.

group (NMe ) accomplished the transformation with 73%

eﬃciency (18). Importantly, the primary amines, for instance,

cyclohexylamino (NHCy) groups, promoted the reaction in

good yields (19). It should be pointed out that 2-

methylaminopyridine gave a relatively low yield (21) because

this product would further be dimerized, forming a hydrazine

product which was similar to the results of our previous

study. Remarkably, the aromatic p-chlorophenylamino

NHAr) group also promoted the desired transformation in

6% yield (20). However, the hydroxyl, methoxy, and

acetamide failed to deliver the targeted products (22, 23,

and 25). Very interestingly, if the two methoxy groups were

preinstalled at the 2- and 6-position of pyridine, the electrolysis

resulted in extremely high eﬃciency with an isolated yield of

(

addition, when a volatile corrosive was used and toxic liquid

bromine was used as the corresponding brominating reagent, a

moderate yield was obtained. Then a series of cyclic

voltammetry (CV) experiments were carried out (Figure 1).

It can be seen that the substrate, 2-aminopyridine, displayed no

oxidation peak in the range of 0 to 2 V. In sharp contrast,

TBABr exhibited two oxidation peaks at 0.93 and 1.31 V,

5% (24). It is worth noting that pyridine derivatives have

been used as a ligand in the palladium-catalyzed reaction,

which indicated that our protocol might be potentially applied

−

•

corresponding to the two redox couples Br /Br and Br /Br ,

respectively. Interestingly, when 2-aminopyridine was mixed

with the TBABr, only one oxidation peak for the couple of

for the ligand modiﬁcation.

Then, the gram-scale reaction with 10 mmol setup was

performed using RVC and nickel foam as the anode and

−

•

Br /Br remained.

The Journal of Organic Chemistry

J. Org. Chem. XXXX, XXX, XXX−XXX

Note

magnetic resonance spectra were recorded on a Bruker Advance 400

(

400 MHz) NMR spectrometer, and H NMR spectra are reported in

units of parts per million (ppm) relative to tetramethylsilane (0 ppm)

or CDCl (7.26 ppm). Multiplicities were given as bs (broad singlet),

s (singlet), d (doublet), t (triplet), q (quartet), dd (doublets of

doublet), dt (doublets of triplet), or m (multiplet). C NMR spectra

were recorded on a Bruker Advance 500 (126 MHz) NMR

spectrometer and reported in ppm relative to CDCl (77.0 ppm).

CV determination was performed on CHI 760E (CH Instruments,

Inc.) with glassy carbon as the working electrode, Ag/Ag as reference

electrode, and a platinum wire as the counter electrode. The

instrument for bulk electrolysis is a dual display potentiostat

(

DJS292B) (Shanghai Xinrui Instruments Co., Ltd.). The GC/MS

instrument is Shimadzu GCMS-TQ8040, and the autosampler is

AOC-20i (Shimadzu Enterprise Management (China) Co., Ltd.)

Procedure for the Synthesis of Substrates (28). A solution of 2-

bromopyridine (9.5 g, 60 mmol) in cyclohexylamine (13.9 g, 140

mmol) was heated in an oil bath at 140 °C for 93 h. After cooling, the

reaction mixture was extracted with water (100 mL) and chloroform

(

3 × 50 mL). The combined chloroform extracts were washed with

Figure 1. CV Investigation

water (2 × 10 mL), concentrated, and ﬁltered through a silica gel

column to obtain the desired product. N-Cyclohexylpyridin-2-amine

(

28). White solid. H NMR (400 MHz, CDCl ) δ 8.05 (d, J = 4.5 Hz,

Based on the above experimental results and previous

reports, a plausible reaction mechanism was proposed in

Scheme 5. First, bromine anion was oxidized to the bromine

1H), 7.38 (t, J = 8.4 Hz, 1H), 6.51 (t, J = 6.0 Hz,, 1H), 6.35 (d, J = 8.4

Hz, 1H), 4.42 (s, 1H), 3.57−3.46 (m, 1H), 2.07−1.99 (m, 2H),

.78−1.72 (m, 2H), 1.68−1.60 (m, 1H), 1.46−1.33 (m, 2H), 1.28−

.14 (m, 3H). C{ H} NMR (126 MHz, CDCl ): δ 158.2, 148.3,

Scheme 5. Proposed Mechanism

37.3, 112.3, 106.7, 50.1, 33.4, 25.8, 24.9.

Procedure for Gram-Scale Synthesis of 1 (Scheme 3). The

electrolysis was carried out in an undivided cell equipped with RVC

100 PPI) as the anode 50 mm × 20 mm × 3 mm) and Ni foam as

(

the cathode (50 mm × 20 mm × 1 mm). To a solution of 2-

aminopyridine (10 mmol, 1 equiv) in MeCN−HOAc (80/10 mL)

were sequentially added TBABr (20 mmol, 2 equiv) and LiClO (0.1

M) to the reaction mixture with stirring at 25 °C under N₂

atmosphere. Electrolysis was started with a constant current of 25

mA, which was then maintained for 38 h. When the reaction was

ﬁnished, concentrated under vacuum. The crude reaction mixture was

puriﬁed by column chromatography on silica gel (petroleum ether/

EtOAc) to give 2-amino-5-bromopyridine (1). In this large-scale

reaction, the current density remained the same as that of the small-

scale reaction.

radical at the anode. Secondary, combination of the nascent

bromine radical forming the bromine was promoted by

following the fast aromatic electrophilic substitution of

pyridine derivatives providing intermediate A. Then deproto-

nation of intermediate A accomplished the desired products.

At the same time, reduction of protons at the cathode released

the hydrogen as the byproduct, which is a clean energy

molecule.

Conversion of the Orienting Eﬀect Group Experiments

(

Scheme 3). 2-Amino-5-bromopyridine (0.5 mmol) and benzyl-

triethylammonium chloride (2.25 mmol, 4.5 equiv) were added to the

absolute ethanol solvent (5 mL) and stirred, and then tert-butyl nitrite

(

5 mmol, 10 equiv) was added dropwise under a nitrogen

In summary, we have developed a novel direct electro-

chemical bromination method for the pyridine derivatives at

the meta-position under a catalyst- and oxidant-free system.

Through constant current electrolysis, the inexpensive and safe

bromide salt was demonstrated as the brominating source at

room temperature. A wide range of brominated pyridine

derivatives was constructed in good to excellent yields.

Combined with the installation and the removing step, this

approach represents an economical, user-friendly, and environ-

mentally benign method for the selective meta-bromination of

pyridines.

atmosphere. The reaction process was always kept at room

temperature and monitored by TLC. After completion, the reaction

was quenched by addition of an aqueous NaHCO solution. The

product was extracted with dichloromethane. The organic extract was

washed with brine, dried over anhydrous magnesium sulfate, and

concentrated in vacuo. The residue was subjected to ﬂash

chromatography to obtain 5-bromo-2-chloropyridine. 5-Bromo-2-

chloropyridine (26) White solid, (74.6 mg, 77%) (petroleum

ether/ethyl acetate = 20:1). H NMR (400 MHz, CDCl ): δ 8.42 (s,

H), 7.74 (d, J = 7.4 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H). C{ H}

NMR (126 MHz, CDCl ): δ 150.7, 150.1, 141.3, 125.7, 119.2.

Procedure for the Control Experiment (Scheme 4). To a

solution of 2-aminopyridine (0.5 mmol, 1 equiv) in MeCN−HOAc

EXPERIMENTAL SECTION

(

8/1 mL) were sequentially added Br (0.5 mmol, 1 equiv) and

■

General Experimental Information. All reagents were pur-

chased without further puriﬁcation unless otherwise noted. All

glassware was oven-dried at 120 °C for hours and cooled to room

temperature. RVC (10 mm × 10 mm × 3 mm 100 PPI) and platinum

plates (10 mm × 10 mm × 0.1 mm) were used as the anode and

cathode, respectively. Analytical thin-layer chromatography (TLC)

was conducted with TLC silica gel GF254 under UV irradiation. Flash

column chromatography was performed using silica gel 300, and

columns were packed according to the dry or wet method. Nuclear

LiClO

(0.1 M) to the reaction mixture with stirring at 25 °C under

atmosphere. Then the reaction was maintained for 12 h. When the

reaction was ﬁnished, the mixture was concentrated under vacuum.

The crude reaction mixture was puriﬁed by column chromatography

on silica gel (petroleum ether/EtOAc) to give the corresponding

product.

General Procedure for the Electrochemical Bromination.

The electrolysis was carried out in an undivided cell equipped with

RVC (100 PPI) as the anode 10 mm × 10 mm × 3 mm) and Pt as the

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

https://pubs.acs.org/doi/10.1021/acs.joc.1c00923.

Note

cathode (10 mm × 10 mm × 0.1 mm). To a solution of 2-

aminopyridine (0.5 mmol, 1 equiv) in MeCN−HOAc (8−1 mL)

2-Amino-4-methyl-5-bromopyridine (11). White solid (56.1

mg, 60%) (petroleum ether/ethyl acetate = 5:1). H NMR (400

MHz, CDCl ): δ 8.06 (s, 1H), 6.39 (s, 1H), 4.51 (bs, 2H), 2.26 (s,

3H). C{ H} NMR (126 MHz, CDCl ): δ 157.5, 148.9, 148.1, 111.7,

were sequentially added TBABr (0.75 mmol, 1.5 equiv) and LiClO

(

0.1 M) to the reaction mixture with stirring at 25 °C under N₂

atmosphere. Electrolysis was started with a constant current of 5 mA,

which was then maintained for 8 h. When the reaction was ﬁnished,

the mixture was concentrated under vacuum. The crude reaction

mixture was puriﬁed by column chromatography on silica gel

110.3, 22.3.

2-Amino-6-methyl-5-bromopyridine (12). White solid (50.6

mg, 54%) (petroleum ether/ethyl acetate = 5:1). H NMR (400

MHz, CDCl ): δ 7.49 (d, J = 8.5 Hz, 1H), 6.24 (d, J = 8.5 Hz, 1H),

4.42 (bs, 2H), 2.48 (s, 3H). C{ H} NMR (126 MHz, CDCl ): δ

(

petroleum ether/EtOAc) to give the corresponding product.

General Procedure for the Electrochemical Chlorination

156.8, 155.1, 141.3, 108.7, 107.6, 24.5.

2-Amino-3-methoxy-5-bromopyridine (13). White solid (70.6

mg, 70%) (petroleum ether/ethyl acetate = 10:1). H NMR (400

and Iodination. The electrolysis was carried out in an undivided cell

equipped with RVC (100 PPI) as the anode 10 mm × 10 mm × 3

mm) and Pt as the cathode (10 mm × 10 mm × 0.1 mm). To a

solution of 2-aminopyridine (0.5 mmol, 1 equiv) in MeCN−HOAc

MHz, CDCl ): δ 7.70 (d, J = 1.4 Hz, 1H), 6.99 (d, J = 1.4 Hz, 1H),

4.70 (bs, 2H), 3.83 (s, 3H). C{ H} NMR (126 MHz, CDCl ): δ

(

8−1 mL) were sequentially added TBACl or TBAI (0.75 mmol, 1.5

48.9, 142.7, 138.9, 118.2, 107.0, 55.6.

2-Amino-4-methoxy-5-bromopyridine (14). Light yellow solid

equiv) and LiClO (0.1 M) to the reaction mixture with stirring at 25

C under N atmosphere. Electrolysis was started with a constant

(71.7 mg, 71%) (petroleum ether/ethyl acetate = 1:1). H NMR (400

current of 5 mA, which was then maintained for 8 h. When the

reaction was ﬁnished, the original solution was detected by GC−MS,

but the targeted product was not detected.

MHz, CDCl ): δ 7.99 (s, 1H), 5.99 (s, 1H), 4.37 (bs, 2H), 3.85 (s,

H). C{ H} NMR (126 MHz, CDCl ): δ 162.9, 159.4, 149.9, 99.3,

1.7, 55.8.

-Amino-5-bromopyridine (1). Light yellow solid (80.1 mg,

-Amino-3-methoxycarbonyl-5-bromopyridine (15). White

3%) (petroleum ether/ethyl acetate = 10:1). H NMR (400 MHz,

solid (80.6 mg, 70%) (petroleum ether/ethyl acetate = 10:1). H

CDCl ): δ 8.08 (s, 1H), 7.48 (d, J = 8.7 Hz, 1H), 6.40 (d, J = 8.7 Hz,

NMR (400 MHz, CDCl ): δ 8.24 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.4

H), 4.52 (bs, 2H). C{ H} NMR (126 MHz, CDCl ): δ 157.0,

Hz, 1H), 6.45 (bs, 2H), 3.89 (s, 3H). C{ H} NMR (126 MHz,

48.6, 140.1, 110.0, 108.2.

CDCl ): δ 166.4, 157.9, 154.2, 141.8, 107.3, 105.9, 52.2.

-Amino-3-chloro-5-bromopyridine (2). Light yellow solid

-Amino-5-chloro-3-bromopyridine (17). Brown solid (58.6 mg,

7%) (petroleum ether/ethyl acetate = 20:1). H NMR (400 MHz,

(

81.4 mg, 78%) (petroleum ether/ethyl acetate = 10:1). H NMR

(

400 MHz, CDCl ): δ 8.01 (s, 1H), 7.63 (s, 1H), 4.98 (bs, 2H).

CDCl ): δ 7.96 (d, J = 2.1 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 5.08 (bs,

C{ H} NMR (126 MHz, CDCl ): δ 153.6, 146.9, 138.8, 115.4,

2H). C{ H} NMR (126 MHz, CDCl ): δ 154.2, 145.3, 139.6, 120.3,

07.1.

104.1.

-Amino-4-chloro-5-bromopyridine (3). Light yellow solid

2-Dimethylamino-5-bromopyridine (18). White solid (72.7 mg,

73%) (petroleum ether/ethyl acetate = 10:1). H NMR (400 MHz,

(

78.9 mg, 76%) (petroleum ether/ethyl acetate = 10:1). H NMR

400 MHz, CDCl ): δ 8.17 (s, 1H), 6.64 (s, 1H), 4.61 (bs, 2H).

CDCl ): δ 8.16 (d, J = 1.9 Hz, 1H), 7.47 (dd, J = 9.0, 2.3 Hz, 1H),

C{ H} NMR (126 MHz, CDCl ): δ 158.0, 150.6, 144.6, 109.5,

6.39 (d, J = 9.0 Hz, 1H), 3.04 (s, 6H). C{ H} NMR (126 MHz,

08.6.

-Amino-6-chloro-5-bromopyridine (4). Oﬀ-white solid (66.3

CDCl ): δ 157.8, 148.3, 139.4, 107.2, 106.0, 38.2.

2-Cyclohexylamino-5-bromopyridine (19). White solid (75.9

mg, 60%) (petroleum ether/ethyl acetate = 10:1). H NMR (400

mg, 64%) (petroleum ether/ethyl acetate = 10:1). H NMR (400

MHz, CDCl ): δ 7.57 (d, J = 8.5 Hz, 1H), 6.31 (d, J = 8.5 Hz, 1H),

MHz, CDCl ): δ 8.07 (s, 1H), 7.46 (d, J = 6.9 Hz, 1H), 6.29 (d, J =

.61 (bs, 2H). C{ H} NMR (126 MHz, CDCl ): δ 157.0, 148.3,

43.2, 108.4, 106.1.

8.9 Hz, 1H), 4.60 (s, 1H), 3.55−3.40 (m, 1H), 2.08−1.95 (m, 2H),

1.80−1.70 (m, 2H), 1.69−1.59 (m, 1H), 1.46−1.33 (m, 2H), 1.28−

-Amino-3,5-dibromopyridine (5). White solid (104.9 mg, 83%)

1.17 (m, 3H). C{ H} NMR (126 MHz, CDCl ): δ 156.7, 148.8,

(

petroleum ether/ethyl acetate = 20:1). H NMR (400 MHz,

139.6, 108.2, 106.3, 50.4, 33.2, 25.7, 24.8.

2-(4-Chlorophenylamino)-5-bromopyridine (20). Light yellow

solid (93.6 mg, 66%) (petroleum ether/ethyl acetate = 20:1). H

CDCl ): δ 8.05 (d, J = 1.8 Hz, 1H), 7.77 (d, J = 1.9 Hz, 1H), 5.00 (bs,

H). ¹C{ H} NMR (126 MHz, CDCl ): δ 154.3, 147.4, 142.0, 107.2,

04.5.

NMR (400 MHz, CDCl ): δ 8.22 (s, 1H), 7.56 (dd, J = 8.9, 2.0 Hz,

-Amino-4,5-dibromopyridine (6). Yellow solid (78.4 mg, 62%)

1H), 7.31−7.24 (m, 4H), 6.94 (s, 1H), 6.70 (d, J = 8.8 Hz, 1H).

(

petroleum ether/ethyl acetate = 15:1). H NMR (400 MHz,

C{ H} NMR (126 MHz, CDCl ): δ 154.4, 148.8, 140.3, 138.6,

CDCl ): δ 8.15 (s, 1H), 6.81 (s, 1H), 4.51 (bs, 2H). C{ H} NMR

129.4, 128.1, 121.6, 110.0, 109.6.

(

126 MHz, CDCl ): δ 157.6, 150.1, 135.4, 112.8, 110.9.

2-Methylamino-5-bromopyridine (21). Brown solid (25.9 mg,

-Amino-5,6-dibromopyridine (7). Oﬀ-white solid (62.6 mg,

8%) (petroleum ether/ethyl acetate = 20:1). H NMR (400 MHz,

0%) (petroleum ether/ethyl acetate = 20:1). H NMR (400 MHz,

CDCl ): δ 8.10 (d, J = 2.2 Hz, 1H), 7.48 (dd, J = 8.8, 2.5 Hz, 1H),

CDCl ): δ 7.53 (d, J = 8.5 Hz, 1H), 6.34 (d, J = 8.5 Hz, 1H), 4.63 (bs,

6.29 (d, J = 8.8 Hz, 1H), 4.63 (bs, 1H), 2.89 (d, J = 4.8 Hz, 3H).

H). ¹C{ H} NMR (126 MHz, CDCl ): δ 156.8, 142.7, 141.0, 109.5,

08.6.

C{ H} NMR (126 MHz, CDCl ): δ 158.1, 148.6, 139.7, 107.6,

06.8, 29.1.

-Amino-4-ﬂuoro-5-bromopyridine (8). White solid (72.1 mg,

-Bromo-2,6-dimethoxypyridine (24). Colorless liquid (104.6

5%) (petroleum ether/ethyl acetate = 5:1). H NMR (400 MHz,

mg, 95%) (petroleum ether/ethyl acetate = 50:1). H NMR (400

MHz, CDCl ): δ 7.61 (d, J = 8.3 Hz, 1H), 6.21 (d, J = 8.3 Hz, 1H),

CDCl ): δ 8.11 (d, J = 9.5 Hz, 1H), 6.26 (d, J = 9.9 Hz, 1H), 4.65 (bs,

H). ¹C{ H} NMR (126 MHz, CDCl ): δ 164.7, 159.7, 159.6, 151.5,

51.5, 96.2, 96.1, 96.0.

.97 (s, 3H), 3.88 (s, 3H). C{ H} NMR (126 MHz, CDCl ): δ

162.1, 158.4, 143.6, 102.7, 95.4, 54.2, 53.8.

-Amino-3-ﬂuoro-5-bromopyridine (9). White solid (57.9 mg,

0%) (petroleum ether/ethyl acetate = 10:1). H NMR (400 MHz,

ASSOCIATED CONTENT

CDCl ): δ 7.92 (s, 1H), 7.36 (d, J = 9.8 Hz, 1H), 4.73 (bs, 2H).

■

C{ H} NMR (126 MHz, CDCl ): δ 147.2, 145.1, 143.5, 143.4,

sı

* Supporting Information

24.7, 124.6, 106.2.

The Supporting Information is available free of charge at

2-Amino-3-methyl-5-bromopyridine (10). Oﬀ-white solid (61.8

mg, 66%) (petroleum ether/ethyl acetate = 5:1). H NMR (400

MHz, CDCl ): δ 7.96 (d, J = 1.0 Hz, 1H), 7.37 (s, 1H), 4.51 (bs,

General information, characterization data, experimental

procedures, and H and C NMR spectra (PDF )

H), 2.10 (s, 3H). C{ H} NMR (126 MHz, CDCl ): δ 155.8,

46.0, 139.8, 118.6, 108.4, 17.0.

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

https://pubs.acs.org/10.1021/acs.joc.1c00923

Note

AUTHOR INFORMATION

Corresponding Authors

■

Notes

Wei Gao − Shandong Provincial Key Laboratory of Molecular

Engineering, School of Chemistry and Chemical Engineering,

Qilu University of Technology (Shandong Academy of

Sciences), Jinan 250353, People’s Republic of China; Archives

of Qilu University of Technology (Shandong Academy of

Sciences), Jinan 250353, People ’s Republic of China;

Email: gaowei161212@163.com

Jianbin Chen − Shandong Provincial Key Laboratory of

Molecular Engineering, School of Chemistry and Chemical

Engineering, Qilu University of Technology (Shandong

Academy of Sciences), Jinan 250353, People’s Republic of

China; State Key Laboratory of Biobased Material and

Green Papermaking, Qilu University of Technology

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We greatly appreciate the ﬁnancial support from the National

Natural Science Foundation of China (Nos. 21801144,

52072190, 22073053), the Youth Innovative Talents Recruit-

ment and Cultivation Program of Shandong Higher Education,

the Natural Science Foundation of Shandong Provincie (Nos.

ZR2018BB017, ZR2020QB114, and ZR2020QB008). The

Project Supported by the Foundation (No. ZZ20190312) of

State Key Laboratory of Biobased Material and Green

Papermaking, Qilu University of Technology (Shandong

Academy of Sciences), the Program for Scientiﬁc Research

Innovation Team in Colleges and Universities of Shandong

Province, and Young Taishan Scholar Program of Shandong

Province (No. tsqn201909139).

(

Shandong Academy of Sciences), Jinan 250353, People’s

Republic of China; orcid.org/0000-0003-1104-7237;

Email: jchen@qlu.edu.cn

Authors

Yanwei Wu − Shandong Provincial Key Laboratory of

Molecular Engineering, School of Chemistry and Chemical

Engineering, Qilu University of Technology (Shandong

Academy of Sciences), Jinan 250353, People’s Republic of

China

Shanghui Xu − Shandong Provincial Key Laboratory of

Molecular Engineering, School of Chemistry and Chemical

Engineering, Qilu University of Technology (Shandong

Academy of Sciences), Jinan 250353, People’s Republic of

China

Hong Wang − Shandong Provincial Key Laboratory of

Molecular Engineering, School of Chemistry and Chemical

Engineering, Qilu University of Technology (Shandong

Academy of Sciences), Jinan 250353, People’s Republic of

China

Dongxu Shao − Shandong Provincial Key Laboratory of

Molecular Engineering, School of Chemistry and Chemical

Engineering, Qilu University of Technology (Shandong

Academy of Sciences), Jinan 250353, People’s Republic of

China

Qiqi Qi − Shandong Provincial Key Laboratory of Molecular

Engineering, School of Chemistry and Chemical Engineering,

Qilu University of Technology (Shandong Academy of

Sciences), Jinan 250353, People’s Republic of China

Yi Lu − Shandong Provincial Key Laboratory of Molecular

Engineering, School of Chemistry and Chemical Engineering,

Qilu University of Technology (Shandong Academy of

Sciences), Jinan 250353, People’s Republic of China

Li Ma − Shandong Provincial Key Laboratory of Molecular

Engineering, School of Chemistry and Chemical Engineering,

Qilu University of Technology (Shandong Academy of

Sciences), Jinan 250353, People’s Republic of China

Jianhua Zhou − Shandong Provincial Key Laboratory of

Molecular Engineering, School of Chemistry and Chemical

Engineering, Qilu University of Technology (Shandong

Academy of Sciences), Jinan 250353, People’s Republic of

China

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