Preparation of 2-chloropyridine

Article abstract of DOI:10.1081/SCC-100105130

Regiospecific chlorination of pyridine-N-oxide to give 2-chloropyridine was achieved in 90% yield with 99.2% selectivity by treatment with phosphorus oxychloride in the presence of a stoichiometric amount of triethylamine. Other chlorinating agents such as sulfuryl chloride, p-toluenesulfonyl chloride, trichloroacetyl chloride, benzenesulfonyl chloride and methanesulfonyl chloride produced 2-chloropyridine also under these conditions, albeit in moderate yield.

Full text of DOI:10.1081/SCC-100105130

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PREPARATION OF 2-CHLOROPYRIDINE
Jae-Chul Jung a , Young-Jo Jung a & Oee-Sook Park b
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)
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
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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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
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
(ꢀC)
Time
(hour) Solvents
Yieldb
(%)
Selectivityc
(%)
Reagents
Base
none
Sulfuryl
chloride
Sulfuryl
chloride
Thionyl
chloride
Thionyl
chloride
Phosphorus
oxychloride
Phosphorus
oxychloride
Phosphorus
oxychloride
Chloroacetyl
chloride
Methanesulfonyl
chloride
Benzenesulfonyl
chloride
40
40
80
80
90
80
40
40
40
40
40
16
3
CH2Cl2
CH2Cl2
DMF
56
64
48
52
36
84
90
59
73
76
80
45
78
60
66
61
82
99.2
66
89
86
79
Et3N
none
6
Et3N
none
3
DMF
24
3
dioxane
DMF
K2CO3
Et3N
Et3N
Et3N
Et3N
Et3N
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1
3
3
p-Toluenesulfonyl
chloride
3
aTemperature; b Isolated yields. The product showed spectral data in accord with the
c
literature10 values; 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
13C 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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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
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 10ꢀC 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 10ꢀC 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 176–177ꢀC/
760 torr (lit.12 166ꢀC/714 torr, lit.13 173–175ꢀC/760 torr); IR (nmax, KBr)
3053, 1578, 764, 725 cmꢁ1
;
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
REFERENCES
2511
1. Tamura; Mitsuhiko; Kasuga; Juzo; Watanabe; Naomichi. Jpn. Kokai
Tokkyo Koho JP 07, 206, 821 [95, 206, 821]; [Chem. Abstr. 1995, 123,
256534q].
2. a) Umemoto, T.; Tomtzawa, G. Tetrahedron Lett. 1987, 28, 2705. b)
Hebel, O.; Rozen, S. J. Org. Chem. 1988, 53, 1123.
3. a) Ash, M.L.; Pew, R.G. J. Heterocyclic Chem. 1981, 18, 939. b)
Mittelbach, M. Synthesis 1988, 479. c) Singh, B.; Lesher, G.Y.;
Pennock, P.O. J. Heterocyclic Chem. 1990, 27, 1665. d) Kaufmann,
D.; Jelich, K. Eur. Pat. 1992, 463, 464; [Chem. Abstr. 1992, 116,
106114u]. e) Hurst, D. T. Adv. Heterocyclic Chem. 1993, 58, 227.
4. Constable, E.C.; Seddon, K.R. Tetrahedron 1983, 39, 291.
5. Faeh, J.; Grieder, A. Eur. Pat. 1983, 72, 777; [Chem. Abstr. 1983, 99,
22326 g].
6. Koenig, T.; Wieczorek, J.S. J. Org. Chem. 1968, 33, 1530.
7. Vozza, J. J. Heterocyclic Chem. 1962, 27, 3856.
8. Matsumura, E. J. Chem. Soc. Japan, Pure Chem. Sect. 1953, 74, 363.
9. Yamanaka, H.; Arak, T.; Sakamoto, T. Chem. Pharm. Bull. 1988,
36, 2244.
10. Friebolin, H. Basic One- and Two-Dimensional NMR Spectroscopy,
Second, enlarged ed. VCH Publisher, New York, 1993, 129.
11. Perrin, D.D.; Armarego, L.F.; Perrin, D.R. Purification of Laboratory
Chemicals. 2nd ed. Pergamon Press, New York, 1980.
12. Von Pechmann, H.; Baltzer, O. Ber. Dtsch. Chem. Ges. 1891, 24, 3148.
13. Kasturi, T.R.; Jois, H.R. Y.; Mathew, L. Synthesis 1984, 743.
Received in the USA November 10, 2000

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