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PREPARATION OF 2-CHLOROPYRIDINE
a a b
Jae-Chul Jung , Young-Jo Jung & Oee-Sook Park
a
Department of Chemistry, College of Natural Sciences, Chungbuk National University,
Cheongju, Chungbuk, 361-763, Korea
b
Department of Chemistry, College of Natural Sciences, Chungbuk National University,
Cheongju, Chungbuk, 361-763, Korea

Version of record first published: 09 Nov 2006.

To cite this article: Jae-Chul Jung, Young-Jo Jung & Oee-Sook Park (2001): PREPARATION OF 2-CHLOROPYRIDINE, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:16, 2507-2511

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 SYNTHETIC COMMUNICATIONS, 31(16), 2507–2511 (2001)
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PREPARATION OF 2-CHLOROPYRIDINE

Jae-Chul Jung, Young-Jo Jung, and Oee-Sook Park*

Department of Chemistry, College of Natural Sciences,

Chungbuk National University, Cheongju 361-763,
Chungbuk, Korea

ABSTRACT

Regiospecific chlorination of pyridine-N-oxide to give

2-chloropyridine was achieved in 90% yield with 99.2% selec-
tivity by treatment with phosphorus oxychloride in the pres-
ence of a stoichiometric amount of triethylamine. Other
chlorinating agents such as sulfuryl chloride, p-toluenesulfo-
nyl chloride, trichloroacetyl chloride, benzenesulfonyl chlo-
ride and methanesulfonyl chloride produced 2-chloropyridine
also under these conditions, albeit in moderate yield.

2-Chloropyridine derivatives are useful for the synthesis of pharma-

ceutical compounds and dyes.1 The two most commonly used methods
for the synthesis of 2-chloropyridine are the direct chlorination of pyridine
with acetyl hypochlorite,2 which is unsatisfactory in yield, and the chlorina-
tion of pyridine-N-oxide using POCl3,3 SO2Cl2,4 phosgene in DMF,5
trichloroacetyl chloride,6 benzenesulfonyl chloride7 or p-toluenesulfonyl
chloride.8 The yields for the reactions using trichloroacetyl chloride

*Corresponding author.

2507

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2508 JUNG, JUNG, AND PARK

and the sulfonyl chlorides were acceptable but the waste disposal
problems associated with the organic chlorinating agents and their
higher cost over inorganics precluded their use in the preparation of large
quantities of 2-chloropyridine. The reaction between POCl3 and pyridine-
N-oxide produces a mixture of 2-chloropyridine and 4-chloropyridine
approximately in the ratio of 7:3 in around 70% yield.9 Recovery
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of pure 2-chloropyridine is not very effective because of difficult separation.

A mechanism involving an addition-elimination sequence was proposed
to account for the reaction of pyridine-N-oxide with POCl3. The oxygen
of pyridine-N-oxide is coordinated with phosphorus of POCl3. This
complexation activates the adjacent carbon atom to chloride ion
attack. Then elimination of phosphorus moiety from this system leads
to overall substitution of hydrogen by chlorine. Considering this reac-
tion mechanism, addition of a stoichiometric amount of base such
as triethylamine should promote the elimination of hydrogen at C-2 and
phosphorus moiety and result in getting higher yield and selectivity
(Scheme).

Scheme.

An evalution of several potential chlorinating agents was under-

taken and the results are shown in the Table. We now wish to report
the conversion of pyridine-N-oxide to 2-chloropyridine utilizing phos-
phorus oxychloride in the presence of a stoichiometric amount of triethyl-
amine.
The chlorination of pyridine-N-oxide with sulfuryl chloride and thio-
nyl chloride in the presence or absence of base gave disappointingly low
yields and selectivities. The reactions of pyridine-N-oxide with p-toluene-
sulfonyl chloride, chloroacetyl chloride, benzenesulfonyl chloride and
methanesulfonyl chloride in the presence of triethylamine gave us 2-chloro-
pyridine in moderate yield and selectivity, whereas phosphorus oxychloride
in the presence of triethylamine gave a 90% yield with 99.2% selectivity. The
latter reaction doesn’t require any purification method such as distillation or
chromatography.
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PREPARATION OF 2-CHLOROPYRIDINE 2509

Table. Reaction of Pyridine-N-Oxide with Several Chlorinating Agents

Temp.a Time Yieldb Selectivityc

Reagents Base (
C) (hour) Solvents (%) (%)

Sulfuryl none 40 16 CH2Cl2 56 45

chloride
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Sulfuryl Et3N 40 3 CH2Cl2 64 78

chloride
Thionyl none 80 6 DMF 48 60
chloride
Thionyl Et3N 80 3 DMF 52 66
chloride
Phosphorus none 90 24 dioxane 36 61
oxychloride
Phosphorus K2CO3 80 3 DMF 84 82
oxychloride
Phosphorus Et3N 40 1 CH2Cl2 90 99.2
oxychloride
Chloroacetyl Et3N 40 1 CH2Cl2 59 66
chloride
Methanesulfonyl Et3N 40 3 CH2Cl2 73 89
chloride
Benzenesulfonyl Et3N 40 3 CH2Cl2 76 86
chloride
p-Toluenesulfonyl Et3N 40 3 CH2Cl2 80 79
chloride
a
Temperature; b Isolated yields. The product showed spectral data in accord with the
literature10 values; c GC-analyzed selectivity.

In summary, selective chlorination of pyridine-N-oxide to give

2-chloropyridine can be achieved reacting phosphorus oxychloride with
pyridine-N-oxide in the presence of a stoichiometric amount of triethyl-
amine.

EXPERIMENTAL

Thin layer chromatography (TLC) was performed on precoated silica

gel 60 F254 plates from EM reagents and visualized with 254-nm UV light or
ceric sulfate-ammoniummolybdate-sulfuric acid spray. 1H NMR and
13
C NMR spectra were recorded on a Brucker DPX 300 at 300 MHz
and 76 MHz, respectively. The chemical shifts are reported in parts
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2510 JUNG, JUNG, AND PARK

per million (ppm) downfield from tetramethylsilane, and J-values were in Hz.
IR spectra were obtained on a Jasco FT/IR-300E spectrometer. GC analyses
were recorded with a Shimadzu-14-D GC system. When necessary, chemi-
cals were purified according to the reported procedure.11
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General Procedure for the Reaction of Pyridine-N-Oxide with

Chlorinating Agent

A solution of the chlorinating agent (72 mmol) in solvent (32 mL) was
added dropwise at 10
C to a stirred solution of pyridine-N-oxide (5.7 g,
60 mmol) and base (72 mmol) in solvents (48–66 mL). The reaction mixture
was heated for the length of time listed in Table. The mixture was concen-
trated in vacuo and treated with dichloromethane. The product was analyzed
with GC to determine the conversion and selectivity of the reaction.

Preparation of 2-Chloropyridine Reacting Pyridine-N-Oxide and

Phosphorus Oxychloride in the Presence of Triethylamine

A solution of phosphorus oxychloride (18.7 g, 120 mmol) in dichlo-

romethane (50 mL) was added dropwise at 10
C to a stirred solution of
pyridine-N-oxide (9.5 g, 100 mmol) and triethylamine (12.1 g, 120 mmol) in
dichloromethane (76–100 mL). The reaction mixture was stirred for 30 min-
utes at room temperature and then refluxed for 1 h. The mixture was poured
into water (30 mL) and neutralized with 2M NaOH. The organic layer was
separated and aqueous layer was extracted with dichloromethane. The com-
bined dichloromethane layer was washed with brine, dried and concentrated
at reduced pressure to give colorless liquid (10.2 g, 90%). In the GC analysis,
the product exhibited 99.2% selectivity to 2-chloropyridine. Bp 176–177
C/
760 torr (lit.12 166
C/714 torr, lit.13 173–175
C/760 torr); IR (nmax, KBr)
3053, 1578, 764, 725 cm1; 1H NMR (CDCl3) d 8.56 (dd, J ¼ 4.74 Hz,
J ¼ 1.58 Hz, 1H, C6), 7.98 (ddd, J ¼ 6.67 Hz, J ¼ 4.78 Hz, J ¼ 1.24 Hz, 1H,
C4), 7.52 (dd, J ¼ 7.96 Hz, J ¼ 0.71 Hz, 1H, C3); 7.60 (ddd, J ¼ 7.37 Hz,
J ¼ 4.86 Hz, J ¼ 0.89 Hz, 1H, C5); 13C NMR (CDCl3) d 206.29, 150.83,
140.19, 125.31, 123.67.

ACKNOWLEDGMENT

This work has been supported by the Basic Science Research Institute
Program (BSRI-99-3433), Ministry of Education, Republic of Korea.
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PREPARATION OF 2-CHLOROPYRIDINE 2511

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Received in the USA November 10, 2000

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