34 JOURNAL OF CHEMICAL RESEARCH 2018
m/z calcd for C7H835Cl2NO2: [M + H]+: 207.9927; found: 207.9942; calcd
for C7H835Cl37ClNO2: [M + H]+: 209.9898; found: 209.9916; calcd for
C7H837Cl2NO2: [M + H]+: 211.9871; found: 211.9887.
2,4-dimethoxypyridine (4) was first chlorinated at both C-3 and
C-5 positions to afford 3,5-dichloro-2,4-dimethoxypyridine (5) in
88% yield, with N-chlorosuccinimide (NCS) as the chlorination
reagent. Selective monochlorination at the C-5 position using
NCS was attempted, but the regioselectivity was poor. The main
product was 3-chloro-2,4-dimethoxypyridine instead of 5-chloro-
2,4-dimethoxypyridine (Scheme 2, path a). Sulfuryl chloride,
another widely used chlorination reagent, gave low yields (8–
10%). Compound 5 was hydrolysed in hydrochloric acid to afford
3,5-dichloro-2,4-dihydroxypyridine (6) in 90% yield.
Previous reports revealed that the halogen atoms at the C-3
and C-5 positions behaved rather differently.6 When treated with
concentrated hydrobromic acid, only the halogen atoms at the C-3
position could be removed.6 Thus, den Hertog and co-workers
reported that 5-chloro-2,4-dihydroxypyridine (2) could be prepared
by heating compound 6 with a solution of hydrobromic acid and
sodium bisulfite.6 However, this synthetic procedure needed some
severe conditions, such as high temperature (200 °C) and special
equipment (sealed tube), making this protocol unsuitable for large
scale preparation. It was assumed that the reaction might proceed
by protonation of the enol and then abstraction of the chloride by
bromide ions to reform the pyridine. Since iodide ions exhibit much
stronger nucleophilicity than bromide ions, we thought to improve
the synthetic procedure by using iodide ions as the nucleophiles.
It was found that the C-3 chlorine atom was removed by heating
compound 6 in a mixture of sodium iodide and acetic acid at 60 °C
in excellent yield.
Synthesis of 3,5-dichloro-2,4-dihydroxypyridine (6): Compound 5
(10.0 g, 48.0 mmol) and 3 M hydrochloric acid (50 mL) were added to a
reaction flask. The reaction mixture was heated for 6 h at 70 °C and then
cooled to room temperature to precipitate compound 6. The precipitate
was collected, washed with water (70 mL) and oven-dried to afford 6 as a
colourless solid: Yield 7.8 g (90%); m.p. 298–301 °C (lit.13 298–303 °C);
1H NMR (400 MHz, DMSO-d6): δ 7.61 (s, 1H), 11.89 (br, 2H); 13C NMR
(100 MHz, DMSO-d6): δ 158.6, 158.4, 131.9, 106.2, 105.0; LRMS (ESI)
m/z (%): 180 (100) [M (35Cl2) + 1]+, 182 (65) [M (35Cl, 37Cl) + 1]+, 184 (12)
[M (37Cl2) + 1]+; HRMS (ESI) m/z calcd for C5H435Cl2NO2: [M + H]+:
179.9614; found: 179.9612; calcd for C5H435Cl37ClNO2: [M + H]+: 181.9585;
found 181.9582; calcd for C5H537Cl2NO2: [M + H]+: 183.9557; found:
183.9559.
Synthesis of 5-chloro-2,4-dihydroxypyridine (2):
A mixture of
compound 6 (8.0 g, 44 mmol), acetonitrile (100 mL), acetic acid (3 mL)
and sodium iodide (13.2 g, 88 mmol) was heated for 8 h at 60 °C. Then the
mixture was cooled to room temperature and poured into 10% sodium
thiosulfate solution (200 mL) to precipitate a colourless solid, which was
recrystallised from water to give pure compound 2: Yield 5.6 g (86%); m.p.
272–273 °C (lit.7 273–274 °C); 1H NMR (400 MHz, DMSO-d6): δ 5.70
(s, 1H), 7.51 (s, 1H), 11.29 (br, 2H) ; 13C NMR (100 MHz, DMSO-d6): δ
163.5, 163.2, 134.6, 105.6, 98.7; LRMS (ESI) m/z (%): 146 (100) [M (35Cl
+ 1]+, 148 (30) [M (37Cl) + 1]+; HRMS (ESI) m/z calcd for C5H535ClNO2:
[M + H]+: 146.0003; found: 146.0012; calcd for C5H537ClNO2: [M + H]+:
147.9975; found: 147.9975.
In conclusion, we have developed a convenient three-step
synthetic approach to 5-chloro-2,4-dihydroxypyridine (2) in 68%
overall yield from commercially available 2,4-dimethoxypyridine
(4). This procedure has potential for industrial production with the
advantages of short steps, simple operations and good yield.
Acknowledgements
This research was financially supported by The National Key
Technology R&D Programme (No. 2015BAK45B00). We also
thank the Laboratory of Organic Functional Molecules, the Sino-
French Institute of ECNU for support.
Experimental
Commercial reagents were used without further purification. Melting
points were measured on a SGW X-4 (INESA) melting point apparatus
and are uncorrected. H NMR spectra were recorded on a Bruker DRX-
400 (400 MHz) instrument. 13C NMR spectra were obtained on a JNM-
EX400 (100 MHz) instrument. Mass spectra (MS) were determined on a
Bruker MicroTof II mass spectrometer or a Waters High Resolution UPLC-
TOFMS spectrometer. IR spectra were obtained using KBr disks on a FTIR
Bruker Tensor 27 spectrometer and are given in the ESI for compounds 5, 6
and 2.
Electronic Supplementary Information
The ESI (1H NMR, 13C NMR and IR spectra of compounds 2, 5
1
1
and 6 and the H NMR and 13C NMR spectra of 4) is available
Received 15 September 2017; accepted 27 December 2017
Paper 1705000
Published online: 25 January 2018
Synthesis of 2,4-dimethoxypyridine (4)11
Freshly prepared sodium methoxide (24 g, 0.44 mol) was added to a
solution of 2,4-dichloropyridine (15 g, 0.10 mol) in anhydrous N-methyl-
2-pyrrolidone (80 mL). The resulting mixture was stirred at 120° C for 6
h. The mixture was then cooled to room temperature, diluted with ethyl
acetate (800 mL) and washed with water. The organic layer was dried over
Na2SO4 and concentrated to give 2,4-dimethoxypyridine (4) as a colourless
oil, which was pure enough to use in the next step: Yield 11.2 g (80%);
1H NMR (400 MHz, DMSO-d6): δ 3.80 (s, 3H), 3.84 (s, 3H), 6.33 (d, J =
2.0 Hz, 1H), 6.60 (dd, J = 2.0 Hz, J = 5.6 Hz, 1H), 7.97 (d, J = 5.6 Hz, 1H);
13C NMR (100 MHz, DMSO-d6): δ 167.5, 165.4, 147.4, 106.1, 93.8, 55.3,
53.1; HRMS (ESI) m/z calcd for C7H10NO2: [M + H]+: 140.0706; found:
140.0707.
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